U.S. FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

National Transportation Safety Board Headquarters

429 L'Enfant Plaza

Washington, D.C.

Wednesday, November 14, 2001

8:00 a.m.

BERNARD A. SCHWETZ, D.V.M., Ph.D.

Acting Principal Deputy Commissioner

Food and Drug Administration

CAROL CARMODY

Vice Chairman

National Transportation Safety Board

Chairmen

STEVE GALSON, M.D., M.P.H.

Deputy Director

Center for Drug Evaluation and Research

Food and Drug Administration

DR. VERNON ELLINGSTAD

Director

Office of Research and Engineering

National Transportation Safety Board

Technical Panels

Food and Drug Administration

DR. ROBERT TEMPLE, Director

Office of Medical Policy and

Office of Drug Evaluation I

Food and Drug Administration

DR. CHARLES GANLEY, Director

Division of Over-the-Counter Drug Products

DR. THOMAS LAUGHREN

Supervisory Medical Officer

DR. ROBERT MEYER, Director

Division of Pulmonary and Allergy

Drug Products

DR. RUSSELL KATZ, Director

Division of Neuropharmacological Drug

Products

DR. PAUL ANDREASON, Medical Officer

Division of Neuropharmacological Drug

Products

National Transportation Safety Board

DR. MITCHELL GARBER, Medical Officer

Office of Research and Engineering

PETE KOTOWSKI, Motor Carrier Specialist

Office of Highway Safety

DR. MARGARET SWEENEY

Transportation Research Analyst

Safety Studies Division

Office of Research and Engineering

RAFAEL MARSHALL, Project Manager

Office of Highway Safety

Witnesses

Measuring Impairment

JAMES F. O'HANLON, Ph.D.

Santa Barbara, California

GARY KAY, Ph.D.

Washington Neuropsychological Institute

Washington, D.C.

Measuring Impairment

R. WILLIAM SOLLER, Ph.D.

Senior Vice President and Director

Science and Technology

Consumer Healthcare Products Association

Washington, D.C.

DR. JOHN WEILER

University of Iowa

Iowa City, Iowa

DR. BERT SPILKER, M.D., Vice President

Pharmaceutical Research and Manufacturers

of America

Washington, D.C.

Epidemiology

JUDY A. STEVENS, M.S., M.P.H.

National Center for Injury Prevention

and Control

Division of Unintentional Injury Prevention

Centers for Disease Control

Atlanta, Georgia

WAYNE K. JEFFERY, B.Sc., M.Sc.

Toxicology Services

RCMP Forensic Laboratory

Vancouver, British Columbia

DOUGLAS LAMAR ALLEN

Alcohol and Drug Program Management

Federal Rail Administration

Washington, D.C.

FIONA J. COUPER, Ph.D.

Washington State Toxicological Laboratory

Washington State Patrol

Seattle, Washington

State and Local Government

JON R. MAY, Ph.D., RPh

Consultant Pharmacist

National Association of Boards of Pharmacy

Gaithersburg, Maryland

State and Local Government

WILLIAM GEORGE

Deputy Attorney General

Wilmington, Delaware

Military

COLONEL ARLEEN SAENGER, USAF, MC, CFS

U.S. Air Force

Washington, D.C.

CAPTAIN DWIGHT C. FULTON, MC, USN, FS

U.S. Navy

Washington, D.C.

Education

NATALIE HARTENBAUM, M.D., MPH

Occumedix

Maple Glen, Pennsylvani

KENNETH EDGELL

Office of the Secretary of Transportation

Washington, D.C.

ALLEN PARMET, M.D., MPH

Midwest Occupational Therapy

Kansas City, Missouri

International

ASBJORG S. CHRISTOPHERSEN, PH.D.

Associate Director

National Institute of Forensic Toxicology

Pharmacy

Norway

DR. JOHANN J. deGIER

Ultrecht Institute for Pharmaceutical Science

The Netherlands

JENNIFER BERGIN, Bpharm, MBA

Pharmacy Consultant

Pharmacy Guild of Australia

R. WILLIAM SOLLER, Ph.D.

Senior Vice President and Director

Science and Technology

Consumer Healthcare Products Association

Washington, D.C.

DR. BERT SPILKER, Ph.D., Vice President

Pharmaceutical Research and Manufacturers

of America

Washington, D.C.

MICHAEL WOGALTER, Ph.D.

North Carolina State Unversity

Raleigh, North Carolina

RUTH DAY, Ph.D.

Duke Unversity

Durham, North Carolina

Advocacy Group

KAREN TARNEY

Citizens Against Drug Impaired Drivers

Milwaukee, Wisconsin

Advocacy Group

DAVID WILLIS, President

AAA Foundation for Traffic Safety

Washington, D.C.

NANCY SANDER, President

Allergy and Asthma Network/Mothers of

Asthmatics, Inc.

Fairfax, Virginia

DR. JOHANN J. de GIER

International Council on Alcohol, Drugs,

and Traffic Safety (ICADTS)

Tucson, Arizona

Industry Group

R. WILLIAM SOLLER

Senior Vice President and Director

Science and Technology

Washington, D.C.

STEVE LISTER

LAURA TAUBIN

BILL BRADLEY

Consumer Healthcare Products Association

Washington, D.C.

NEAL THOMAS

American Trucking Association

Alexandria, Virginia

DR. TOM FAULKNER

Air Transport Association

Washington, D.C.

TODD SPENCER

Owner-Operator Independent Drivers Assc.

Grain Valley, Missouri

CAPTAIN JOHN DeLEONARDIS

Liberian International Ship and Corporate

Registry, LLC

Vienna, Virginia

WILLIAM MAHORNEY

American Bus Association

Washington, D.C.

Industry Group

NORM LITTLER

United Motorcoach Association

Alexandria, Virginia

Operator Union Group

KAREN HEAD

Legislative Council

Teamsters

Washington, D.C.

CAPTAIN RANDY POPIEL

Allied Pilots Association

Fort Worth, Texas

ROBERT M. CLARKE

Professional Group

RICHARD GELULA

Executive Director

National Sleep Foundation

Washington, D.C.

DARREL DROBNICH

Senior Director of Government and

Transportation Affairs

Washington, D.C.

Also Present

DR. FRED TILTON

Deputy Federal Air Surgeon

Federal Aviation Administration

NANCY LaMONICA

Office of the Secretary

Department of Transportation

A G E N D A

AGENDA ITEM: PAGE:

Administrative Announcements 9

Dr. Vernon S. Ellingstad

Opening Remarks 11

Dr. Bernard Schwetz

Food and Drug Administration

Carol Carmody 16

National Transportation Safety Board

Introductions 22

Dr. Vernon S. Ellingstad

Witness Panel I - Measuring Impairment 27

Questions from Technical Panel/Parties 55

and Discussion

Audience Discussion 151

Afternoon Session

Witness Panel II - Epidemiology 157

Questions from Technical Panel/Parties 183

and Discussion

Witness Panel III - State and Local Government 221

Questions from Technical Panel/Parties 229

and Discussion

Witness Panel IV - Military 278

Questions from Technical Panel/Parties 289

and Discussion

Adjournment 322

P R O C E E D I N G S

8:00 a.m.

Administrative Announcements

DR. ELLINGSTAD: Good morning.

I think we will begin. We have given people a little extra time to get here and our apologies for the confusion that led some people to the freight elevator and apparently a considerable wait.

Welcome to an unusual meeting that's a joint effort of the U.S. Food and Drug Administration and the National Transportation Safety Board on Transportation Safety and Potentially Sedating or Impairing Medications.

I'm Vern Ellingstad from the National Transportation Safety Board. With me is Dr. Steven Galson from the Food and Drug Administration, and we will try to facilitate the efforts here today and tomorrow.

Before we begin the substance of the meeting, there are a few procedural announcements that we need to make. In the event of an emergency, such as fire, the building alarm system will activate and a voice message will instruct persons to vacate the building. You should proceed to the nearest exit. There are emergency exits up front to the left and to the right of the platform and also at the back of the room.

Also for your convenience, restrooms and telephones are located in the foyer on the left as you exit the room.

To provide an appropriate meeting environment, I'd request that you set your pagers and cell phones to alert you silently to avoid interrupting the meeting. If this is not possible, please turn your device off. If you must use a cell phone, please do it outside of the meeting room.

To begin the meeting, I'd like to introduce Dr. Galson, who will introduce our first greeting from the Food and Drug Administration.

Steve?

DR. GALSON: Thanks very much.

I'm really extremely pleased today to welcome all of you, and I want to start by introducing our Principal Deputy Commissioner for Food and Drug, Dr. Bernard Schwetz.

Dr. Schwetz was from 1999, in September, until January 2001, Acting Deputy Commissioner of Food and Drug, and he served as a senior advisor for Science from September 1999 till June 2000. He was Director of FDA's National Center for Toxicological Research in Jefferson, Arkansas, from 1993 to 1999.

He's a Diplomat of the American Board of Toxicology and an Honorary Diplomat of the American Veterinary Epidemiological Society.

Dr. Schwetz was the Acting Director of the Environmental Toxicology Program at the National Institute for Environmental Health Sciences in Research Triangle Park before coming to FDA in 1993.

Dr. Schwetz is a Member of the National Academy of Science's Institute of Medicine. In addition to numerous other professional awards during his career, Dr. Schwetz received the U.S. Government's 1998 Meritorious Executive Presidential Rank Award.

It's truly a pleasure for me to welcome Dr. Schwetz here today to open up the meeting for the Food and Drug Administration.

Thanks, Vern.

Opening Remarks

DR. SCHWETZ: Thank you, Steven.

Good morning to all of you. First, I'd like to acknowledge the important role that the NTSB plays in our nation's transportation safety and particularly over the past few days with the heroic efforts you're making to investigate the tragic plane crash in New York City on Monday.

As devastating as that accident was, your quick work to investigate the cause has helped to calm Americans' immediate fears. Although the precise cause of the crash is not yet known, it helps to know that it doesn't appear to be another terrorist activity. We certainly wish you every success in that on-going investigation.

From the FDA, we're happy to co-sponsor this first-ever FDA/NTSB Joint Public Meeting. I'm glad to see that our two organizations take this opportunity to work together, to look at the role of sedating or impairing medications in accidents and related injuries.

I'd like to thank Mary Ann Blakey, the recently-appointed Chairman of the National Transportation Safety Board, and Carol Carmody, the Vice Chairman, and Dr. Vernon Ellingstad and his staff at the NTSB for assisting FDA in putting this meeting together, and I would also thank Dr. Ellingstad and Dr. Steven Galson from the FDA for co-chairing the meeting today and tomorrow.

I'm pleased to see the level and range of expertise that is assembled here today on our panels and as witnesses as we consider the issues in front of us. So, thank you all very much for being here.

The FDA is certainly very supportive of NTSB's efforts to improve the safety of our nation's transportation operators, and we look forward to being part of this effort. Our former FDA Commissioner, Dr. Jane Henney, indicated last year that we would take this issue very seriously, and we continue to have this as a high priority.

Today's workshop demonstrates our commitment to consider all perspectives, including those of the transportation industry, other government agencies, and the public. We will also work with the pharmaceutical industry when considering recommendations that relate to labeling changes.

Well, what are the issues that we hope to address in these two days?

First. How can we increase awareness of the public about the possible impairment caused by prescription and over-the-counter drug products?

Second. How can we identify those products that cause impairment?

Third. How can we help the public avoid taking products that will cause impairment while they're driving?

And fourth. Would relabeling those prescription and over-the-counter products help the issue?

By looking at the data available today, we hope to define the magnitude of the public health issue, both for transportation operators and for those with whom they share the roads, rails, skies and the waterways.

We'd like to look at possible mechanisms to screen for effects of time on driving, perhaps by looking at well-established assessment methods to see if they could be used to evaluate operators taking potentially problematic medications.

We want to identify the best ways to communicate the potential risks to the public. If we decide that labeling modifications are one effective way to accomplish this, what changes should be made so that labeling will be more informative to the user?

In closing, let me say that to the extent that drugs we approve are contributing to errors made by vehicle operators, we are very concerned. I assure you that we will take seriously any comments related to this issue, whether the comments come out of this meeting today and tomorrow or whether they are submitted to the docket.

The issues are complex, but they're not insurmountable. So, we want to work together to help find solutions.

Thanks to all of you for participating in this meeting and for contributing your time, expertise and creativity. I'm looking forward to a productive session.

Thank you.

DR. ELLINGSTAD: Thank you, Dr. Schwetz.

I'm pleased now to introduce our Vice Chairman, Ms. Carol Carmody. Ms. Carmody worked for the Federal Aviation Administration from 1977 to 1988, including a tour as Deputy Director of Congressional Services. From 1988 to '94, she was an Aviation Staff Member of the Senate Commerce Committee. From 1994 to 1999, she was the U.S. Representative to the Council of the International Civil Aviation Organization, ICAO, in Montreal.

She was sworn in as the 30th Member of the National Transportation Safety Board in June of 2000 and appointed Vice Chairman on January 19th of 2001. She served a stint this year as Acting Chairman, and she brings a considerable amount of experience to the transportation area.

Carol?

Opening Remarks

MS. CARMODY: Thank you, Vern.

Good morning. I'm Carol Carmody, as Vern said. Mary Ann Blakey was very sorry not to be here this morning. She had looked forward to this. I spoke with her yesterday evening, and, of course, she's occupied in New York but wanted me to send her regards and her wishes for a successful conference.

Before I get started this morning, I wanted to recognize the contributions of a couple of former government servants. Former NTSB Chairman Jim Hall and former FDA Commissioner Dr. Jane Henney. Those two really initiated this concept some time ago, and they deserve credit. I don't know if either is here today, but I did want to mention their names.

Also, the planning has been ably executed by Dr. Vern Ellingstad of our staff and by Dr. Steve Galson of the FDA, who are co-chairs of this conference.

I also appreciate the attendance and the remarks very much of Dr. Schwetz. I appreciate what you said about the NTSB and about our efforts. We all feel that way, too.

Those of us gathered here today come from different sectors of society, from different agencies, and in some cases from different countries, but we all have the same goal, and that's to ensure safe travel for our citizens. Just as in the past, when faced with a problem, we have come together to work towards a unified solution.

Today, we're looking at an issue that we've known about for years: the fact that over-the-counter medicines and prescription drugs contribute to transportation accidents. We've made some recommendations to address certain aspects of this issue. Even so, we've not yet solved it, and it's clear that we need to learn a lot more.

Many medicines have long been known to cause drowsiness. Others may impair an individual's ability to fly an airplane, drive a car, steer a ship or operate a train. In fact, recent studies have shown that several over-the-counter medicines and prescription drugs can adversely affect an individual's performance without him or her being aware of it.

Since 1987, the NTSB has investigated over a 150 accidents in all modes of transportation in which over-the-counter medicines or prescription drugs caused or contributed to the accident. In aviation alone, over-the-counter medicines and prescription drugs played a part in 72 fatal accidents between 1987 and 1995. Since 1995, the numbers have been on the rise.

We at the Safety Board believe that the numbers may be even higher than we realize. Only a small percentage of people are ever tested for such drugs following an accident. So, we believe that they may contribute to more accidents than we're aware of.

So, we're faced with a tough question. How do we reduce the number of accidents caused by such medications when the extent of the problem is unknown? The answer is not simple. We must work together to expand testing programs to educate the public.

Last year, the Board made a number of recommendations, including expanding current toxicological testing requirements to get appropriate samples from fatal transportation accidents, so we could determine what effect these prescriptions and over-the-counter medicines are having.

The Board proposes expanding educational programs and providing better warning labels on the medicines.

All of us here today understand that when education can prevent accidents, it's our responsibility to provide that education to the public. To all of the people operating planes, trains, cars, buses and ships, they deserve to know what effect drugs will have on their performance.

We should also recognize the efforts to date, and there have been many. The Department of Transportation and its many modal administrations as well as many other organizations here today have taken steps to reduce the number of accidents caused by over-the-counter medicines and prescription drugs.

The NTSB commends these efforts. As always, we want more. We recognize that more needs to be done, and we must do it together. Certainly none of us would be here today if we didn't think there was more room for work.

Both the NTSB and the FDA appreciate the attendance of everyone today, the experts, the participants, and those of you in the audience, and I think we're one step closer to a common solution.

Thank you.

DR. ELLINGSTAD: Thank you, Vice Chairman Carmody.

Before we begin, we'll kind of outline the sort of procedures that we will follow today and tomorrow in this public meeting. I'd like to sort of make it as clear as we can what this meeting is and is not.

It is not an adversarial proceedings. It is not a hearing. It is a public meeting designed to elicit information and to provide information that will inform both the FDA and the NTSB with respect to our interests in this particular topic.

The way that the meeting will proceed is through a series of witness panels. The panels, the members of the panels will each make a short presentation and then respond to questions. The questions will be directed by a technical panel composed of staff members from the FDA and the NTSB, and questions will also be solicited from a number of

-- those who are familiar with NTSB proceedings, referred to as parties, and we will in a moment introduce who these parties are.

But each of the party groups representing various constituencies affected by the issues of drugs in transportation safety will have an opportunity to pose questions to the witnesses.

When we have completed that round, and we will try to do that as equitably and fairly as we can, we will pass the questioning back to the Technical Panel. Dr. Galson and I reserve the right to butt in and ask questions, if we desire.

We will also solicit from the audience questions in writing that will be forwarded up here to the podium and whichever of us is not moderating a particular panel will sort those out, and we will pose those questions also to the panel.

Time is of something of an essence, and we will try to maintain a schedule better than our starting time was maintained this morning. So, we would appreciate that all of the presentations as well as the questions be kept concise.

The staff will circulate among the audience and hand out cards that will contain the questions that will be brought up here. So, if you see staff with cards, if you have a question, draw their attention to that and send them up.

Another thing that is a little bit unusual in terms of proceedings that the Board has been involved in is the provision for audience presentations, and there will be two of those. One this morning at approximately 11:15.

Anyone desiring to make a short five-minute presentation should contact the desk in the lobby area, and we will only recognize individuals who have registered to do that, and they will be called on to make those short presentations today at 11:15, and there's also another session that's set aside for that tomorrow.

What I'd like to do, I believe that Dr. Galson has a couple of administrative announcements with respect to the opening of a docket of this meeting, and then I'll ask him to also introduce the FDA members of the Technical Panel. When he's done with that, I'll catch the NTSB members of the panel.

Introductions

DR. GALSON: Great. Thanks.

FDA, in our regulatory capacity, is required to have a copy of all of the presentations in writing and filed to the FDA docket, and the docket number for this meeting is 01N0397. Please make sure you file the copy of your presentation, and if you've not, give a copy to the FDA representatives out at the table.

Also, any special requests for copies of the presentation from this meeting should be asked for at the Registration Table if people in the audience want copies, and they'll be mailed to you at a later date.

We'll put a transcript of the meeting on our FDA website by the middle of December.

I'd like to quickly introduce our Technical Panel that are here from the agency. We've really got an all-star cast of experts sitting up at the table over here, and folks, if you'd just raise your hand, so folks know who you are.

Leading the team is Dr. Robert Temple, who's the Director of two offices in the Drug Center, the Office of Medical Policy and the Office of Drug Evaluation I.

Dr. Robert Meyer is the Director of Pulmonary and Allergy Drug Products. Charlie Ganley is the Director of our Over-the-Counter Drug Products Division. Russell Katz is the Director of our Division of Neuropharmacological Drug Products. Tom Laughren is the Supervisory Medical Officer in the same division, and Paul Andreason is a Medical Officer in the division as well.

So, thank you, FDA experts, for being here, and we look forward to your active participation.

DR. ELLINGSTAD: I'd like to introduce the NTSB's staff who are serving on the Tech Panel and will make themselves known with questions throughout the course of today and tomorrow.

First, Dr. Mitch Garber is the Board Medical Officer, and I'd like to give a special acknowledgement for his very extensive effort in coordinating this whole activity.

Next, Mr. Pete Kotowski, a Motor Carrier Specialist and Accident Investigator with the Board's Office of Highway Safety. Dr. Rafael Marshall, Project Manager and Investigator, also in the Office of Highway Safety, at the NTSB, and Dr. Meg Sweeney, the Transportation Research Analyst in our Safety Studies Division, here at the Safety Board.

I'd like also to acknowledge the participation of the various parties, and what I'd like to do very quickly is go around, and we'll do this in an orderly sort of way to begin with at least, and I'll ask -- we'll go to each of the tables and ask each participant at the various tables to introduce themselves.

I'd like to also mention that in the interest of expediency, what we will ask each of the tables to do is to designate a spokesperson for the purpose of questioning of our witness panels. We aren't going to have an opportunity to go and have everybody at every table ask questions, but if you will provide designated spokesman -- provide your questions to that spokesman, and we can handle the questioning in that particular way. We certainly can rotate that spokesman duty during the course of the two days.

Okay. Let me start over on my right with the Union table. Push the button.

CAPTAIN POPIEL: Randy Popiel, Allied Pilots Association.

DR. ELLINGSTAD: Thank you.

And the Industry Table. Try it again.

MS. TAUBIN: Lorna Taubin, representing the Consumer Healthcare Products Association.

DR. ELLINGSTAD: Okay. And we have another Industry Table, a Transportation Industry Table.

CAPTAIN DeLEONARDIS: Captain John DeLeonardis, representing the Liberian International Ship and Corporate Registry.

MR. SPENCER: Todd Spencer with the Owner Operator Independent Drivers Association.

MR. LITTLER: Norm Littler with the United Motorcoach Association.

MR. MAHORNEY: Bill Mahorney with the American Bus Association.

MR. THOMAS: Neal Thomas with the American Trucking Association.

DR. FAULKNER: Tom Faulkner with the Air Transport Association.

DR. ELLINGSTAD: Thank you.

And the Advocacy Group Table.

MS. TARNEY: Karen Tarney, Citizens Against Drug Impaired Drivers.

MS. CHRISTOPHERSEN: Asbjorg Christophersen from the National Institute of Forensic Toxicology in Norway.

DR. de GIER: Johann de Gier, International Council on Alcohol, Drugs and Traffic Safety.

MS. SANDER: Nancy Sander, Allergy and Asthma Network, Mothers of Asthmatics.

MR. WILLIS: David Willis, AAA Foundation for Traffic Safety.

DR. ELLINGSTAD: Okay. And the Government Table? Why don't we start -- go ahead.

MR. CLARKE: Bob Clarke, U.S. Department of Transportation, Office of the Secretary.

MS. LAMONICA: Nancy Lamonica, Department of Transportation, Office of the Secretary.

MS. STEVENS: Judy Stevens, Centers for Disease Control and Prevention.

DR. ELLINGSTAD: Okay. Thank you.

Okay. Without further ado, we'll go to the Witness Panel, the first Witness Panel dealing with the topic of Measuring Impairment, and what we will do with this panel is kind of go right down from my right to left.

Let me just very quickly introduce and kind of give the rules of engagement for this group. We'll ask you each to confine your set of opening remarks to five minutes, and we'll trust the Technical Panel and the parties to elicit the additional information that you have brought along.

We'll start with Dr. John Weiler from the University of Iowa.

Witness Panel I - Measuring Impairment

DR. WEILER: Are we ready with the slides?

Thank you for the opportunity to be here and talk about the use of driving simulators to measure impairment in driving.

Next slide. There are a variety of medications that may impair performance, and I've listed some of them on this slide, including anabolic steroids, anesthetic agents, anti-anxiety drugs, anti-depressants, caffeine and stimulants, and the remainder of the drugs, one that's very concerning to us and to me as an allergist would be those drugs we use to treat respiratory disease.

We also are concerned about drugs given to the elderly and combinations of drugs and, of course, drugs that may be abused.

Next slide. Now, sedation is the issue, but sedation can be broken into drowsiness and impairment. It's easy to measure drowsiness. It's a subjective feeling, and we record the numbers. It's much more difficult to measure performance impairment, and that is an interference with the ability to perform a task or tasks measured objectively.

If the patient experiences drowsiness only, that's a subjective feeling that's not pleasant, but performance impairment only is a very serious problem because the patient doesn't have the idea that the person is impaired. If the person has both, then hopefully the drowsiness will be a cue not to do the task.

Next slide. We can ask a variety of sample experimental questions, and these are some of the ones that we've asked, such as do first-generation sedating antihistamines cause performance impairment as compared with non-sedating antihistamines, when measured, using a high-fidelity driving simulator, and if yes, can the subjects predict impairment based upon drowsiness or upon their feeling of being impaired?

Next slide. What I would like to show you is a very small video clip of the new National Advanced Driving Simulator that will allow us to do some studies that were not possible before this facility was completed. Let's put the video in.

(Videotape shown)

DR. WEILER: We'll just keep going on with the slides, and hopefully we can come back to that at some time later.

Next slide. Next slide. Unfortunately, that shows you the ability to do some of the tasks that are described on this slide as end points. The fidelity with that simulator will be something that will be unmatched in the future, the ability to look at all of these many end points, including lane tracking, lane excursion. Obviously, it's very important that we keep within our lanes. Steering instability, ability to follow a car. We can measure a variety of end points for that. Curve trajectory, staying within the lane, speed control measures.

Eye tracking is a very important and a very interesting end point that we're looking at with a variety of different new pieces of equipment. The percent of closure of eyes and things that would tell us that someone is impaired and is about to nod off. Head tracking.

Next slide. We can look at responses to events, subtle events, repeated events, and events that are potentially life-threatening, and we can do that in a simulator that we couldn't do on on-the-road driving.

We look at subjective drowsiness, and we correlate that with objective measures, and we correlate subjective feelings of being impaired with subjective drowsiness. Then we look on the other side of subjective feeling of being impaired, and does it correlate with objective measures, and does it correlate with drowsiness?

Next slide. There are a lot of advantages of the use of the National Advanced Driving Simulator and perhaps we can show you actually a picture of it later. We can use realistic crash scenarios, put people in harm's way that we couldn't in on-the-road driving. The tasks are realistic. We can control traffic both in lane and in the oncoming lane and with high-density traffic with people who are impaired. We can look at a variety of weather conditions.

We have a high-fidelity image generator that is a 20/20 image in the center, something that has never been possible before. High-fidelity motion, so the motion is what you would feel in on-the-road driving, and we have tremendous flexibility in designing the scenarios, both rapidly, and they're very realistic, and finally is the fully immersive environment.

Next slide. So, in conclusion, driving simulator studies have been accepted as demonstrating performance impairment. They may be more expensive than other kinds of studies, but the rewards may justify the cost if lives are saved.

The National Advanced Driving Simulator will indeed be a unique facility to study human performance in a variety of settings that have not been possible in the past. It will offer us an opportunity to cross-validate lower-fidelity simulators and other tests.

The bottom line is that driving is a real world task. It's very important to many of us.

DR. ELLINGSTAD: Thank you, Dr. Weiler.

Our next panelist is Dr. James O'Hanlon from Santa Barbara, California.

DR. O'HANLON: Good morning.

Can you hear me? Fine. I have two points to make today; that is, that we have the technology for screening drugs in the registration process. We've had it for nearly 20 years, and this procedure will lead to a labeling system, an example of which that I will show today.

May I have the first -- actually, the second slide. That just says who's talking.

We, beginning in 1981, began developing an over-the-road driving test for assessing the effects of medicinal and recreational drugs. We standardized that test two years later, in 1984, and essentially it has been applied in more than 45 major studies, unchanged ever since.

We've used it with psychiatric patients, depressed and anxious. We've used it with cognitively impaired elderly and mostly with healthy volunteers. The test is recognized by the EMEA, which is the FDA's equivalent in Europe, as valid for assessing the effects of certain drugs, specifically hypnotics and anxiolytics.

May I have the next one, please? I haven't brought pictures of this test because we've done everything we can to make it appear completely naturalistic, both to the subjects of the test and also to the other people in the driving environment with whom they interact.

The safety is supervised in this test by an on-board licensed driving instructor. The test begins with the test subject or patient entering a primary highway into normal traffic and proceeding 50 kilometers, 30 miles, in one direction, exiting and returning and returning 50 kilometers to the origin.

During this time, speed and lateral position of the vehicle are measured by automatic means. The standard deviation of lateral position measured over the entire test is the primary outcome variable. It is a measure of -- combined measure of swerving and weaving, and we call that SDLP from now on.

I'm using one example of the work that we did together in the Netherlands until my leaving in '98. I must add that it continues today under other direction.

The example I've chosen is an example of hypnotic drugs. We have studied nearly every hypnotic drug available in Europe and the United States, and the way we do it is administer the drug to the patient or the volunteer and allow them to sleep. We test -- we have tested patients and volunteers five to 17 hours after drug ingestion.

The experiments. There have been about a dozen in number. They have all followed double-blind placebo and active control designs in a number of different experiments, with an exceptional case of 12, usually 18 to 24. The power for detecting a significant effect of the drug has always been better than 90 percent.

May I have the next one, please? The next one. Now, the reason that we're interested in the residual effects of hypnotic drugs is because we have a little epidemiological information to indicate that that problem is most severe.

Flurazepam or Dalmane, as it's called in the United States, was the first benzodiazepine registered in this country. It has been shown in epidemiological research to increase the risk of an injurious accident more than five times normal, which is the equivalent to driving with a blood alcohol concentration of .95 milligram per milliliter or in the United States term, .09 gram per deciliter.

So, I'm going to be talking in the European units, but if you'd like, just put a zero in front of that 9, and you will have the units here.

In the old dose, Triazolam or Halcion raised the relative risk of injurious accidents more than three times. There is a drug available in Europe but not here. It's supposed to be a slow-acting drug and very safe, according to the manufacturer, but it was shown in England to raise their risk of injurious accident four times, which is the equivalent of a blood alcohol concentration of 0.8.

Next slide, please. I have too much data to discuss in detail. I would just like you to concentrate on the three bars to the right. This is average standard deviation of lateral position SDLP over a one-hour ride, 10 hours in the blue bar after taking the drug, and the red bar, 16 to 17 hours.

These all are hypnotics with very long half life, but I would like to focus on Flurazepam, a drug I already mentioned, Dalmane. We have studied it three times, twice with patients, once with volunteers, and we have measured a greater effect of that drug 10 hours after administration than produced by a blood alcohol concentration of .10 or drunk in every one of the American states. Even 16 to 17 hours after administration, the effect is still greater than a blood alcohol concentration of .05.

I would like to go quickly over the next slide, just actually look at -- glance at it briefly. These are intermediate-acting hypnotics. They have less effect. These are not in the system so long but still, as you see, some of them are impairing the next morning and even in the next afternoon after ingestion.

The next slide, please. Modern hypnotics are very short-acting. The two that are quite popular in the United States, one is Zaleplon or Sonata is the trade name. The other is Zolpidem, ZPD up there, and it is called Ambien in the stores.

When you look at either one of those drugs, the first three bars on the left, 10 hours after ingestion, neither one of them has an effect, and even Zaleplon in 20 milligram dose, which is twice recommended, still has no effect. But how close to the time of awakening can you take it?

I skip over the nasal amitrazalem bars, and going now to where it says in the top, "Five to six hours after administration", we've measured the effect of Zaleplon here and of both 10 and 20 milligram doses. Again, they're not significant. We'll leave the Zoplicone bar. That's a European drug.

Now, far over on the right, here is taking the drug only four hours before the test, and here, you see Zaleplon 10 and 20 milligram have no effect. Zolpidem 10 milligram, the registered dose, has an effect greater than .05 blood alcohol concentration, almost .08, and if you would take twice the dose four hours, you could see that the effect is greater than .10 blood alcohol concentration.

Last slide. From these data, we are able to make pictograms which precisely and informatively allow the user to know what to expect from a hypnotic drug. These are only two categories. We've actually published a six-category system, and it could even be expanded, but in this, for the two examples I've just given of Zaleplon and Zolpidem, we don't know how long it would be dangerous to drive after Zaleplon. We only know that after four hours, it had no effect.

So, we say zero to four hours, you are forbidden to drive, according to our recommendation. After that, you are free to drive for the next 24 hours. With Zolpidem, a very good drug, a very safe drug, still again we haven't tested it before four hours, but we advise people not to drive. We have tested it four to five hours. There was an effect, and so we say all right, from that point until the next time we've tested it and found no effect, you drive with great caution because the effect we anticipate is greater than the blood alcohol concentration of .05, and after that, you're free.

We have done this for many drugs. The worst of them, Dalmane, as I showed you, has red around the clock. You should never drive using that hypnotic in 30 milligram doses. We think this is a reasonable way of portraying crucial information to the patients who use this drug.

Thank you.

DR. ELLINGSTAD: Thank you, Dr. O'Hanlon.

Our next panelist is Dr. Gary Kay from the Washington Neuropsychological Institute in Washington, D.C.

Dr. Kay?

DR. KAY: Good morning, and I appreciate the opportunity to speak to you.

If we can go to the first slide, my comments will be more general on how we measure impairment, what the methodology is and extent to which we have advances in this methodology currently.

I think one of the reasons why we're here, if you'll show the slide, why we're here is that the public has little awareness of the risks associated with taking especially sedating over-the-counter medications, and often, there is a belief that if you don't feel drowsy, that in fact you aren't sedated.

But as Dr. Weiler has shown, go on to the next slide, next slide after that, please, in fact, a depressant medication's effects on the central nervous system could be manifested different ways. In fact, you may feel sleepy. You may feel drowsy. That's your personal experience. Often, people have -- they think the definition of sedation is drowsiness, but it's more.

In fact, there could be changes physiologically in brain activity. There may be a change in your ability to stay awake during the day. There may be a detrimental effect on your performance. In fact, if we are going to evaluate medications and give an honest appraisal about whether a medication is sedating, we must use all of these methods. We must find out do people feel drowsy or sleepy? Are there physiological changes? Are there performance changes?

With respect to self-report measures, commonly we use diary cards. Often, there's too much reliance on diary cards. There are rating scales, visual analog scales. There are newer devices, such as the use of personal data systems, like Palm Pilots, and there's also data we can obtain from prescription event monitoring.

Taking a look at the new methodology of the use of these personal data systems, these provide us with very high subject compliance. You actually program them to inquire of the subject at different points during the day about their current subjective level of sleepiness. You get a time logging of these entries, and there's improved data handling. They were recently demonstrated at the DIA Conference in Denver to be superior to the paper diary.

The problem with self-report measures are that they are subjective. There may be biased reporting. There is poor diary compliance, and as Dr. Weiler pointed out, there's low agreement often with physiological and performance measures.

Somebody may report no self-reported sleepiness, but in fact show physiological impairment or cognitive impairment or in fact driving impairment in the absence of any self-reported sleepiness. We do have physiological measures. I've listed some of them here for you. EEG.

At Georgetown, we've been working with functional brain imaging. Sleep latency testing has been around for awhile, and there's activity monitoring as well.

Here is some data from one of our studies at Georgetown where we are looking for the physiological and subjective. This is night-time, 10 p.m., dosing with Chlorpheniramine. The red is eight milligram, the purple 12 milligram Chlorpheniramine at 10:00.

Looking at the next day, from 9 a.m. till 5 p.m., the number of -- average number of minutes before people fell asleep during naps, and what you're seeing here is that for placebo, we have a normal sleep latency greater than 10 minutes, but for either the eight or 12 milligram Chlorpheniramine, taken 10:00 the night before, the next day, the sleep latencies drop down to six minutes, both statistically significant but clinically meaningful as an evidence of excessive day-time somnolence, and looking to the right, it's indicating that on the Stanford Sleepiness Scale, the subjects who received the eight milligram dose of Chlorpheniramine are reporting no more sleepiness than the patient who received placebo. They had no awareness of their sleepiness.

This is looking at the results from our functional brain imaging. We're looking at changes in brain activation with -- while people are performing a mental arithmetic test after they've been dosed with again eight and then 12 milligram Chlorpheniramine. The white is placebo. This is showing you the brain imaging. The left side shows what activates during training. The right side under retesting with placebo, there's only one-quarter the amount of activation once you've learned to perform an activity in the FMRI.

If you know you're looking at another subject here on the left side that's training, the right side, this is three days of dosing Chlorpheniramine at night, looking at day-time performance in the FMRI, and you're seeing actually five and a half to six times an increase in the amount of brain activation.

Now, those are physiological. Lastly, we have performance measurements, and performance measurements include tests of thinking or cognition, tests of skilled motor activity, psychomotor, and as you've heard from the first two speakers/witnesses, simulation testing.

In terms of what we're doing currently to measure cognitive functioning, we are using a lot of computer-based neuropsychological tests, and these are tests that we initially developed largely to look at early-on chemical defense and did a lot of this work in the Department of Defense.

These methods provide us a number of advantages. There is standardized instructions, standardized presentation of stimuli. There's enhanced sensitivity over traditional paper and pencil-type testing, highly accurate measures of speed and accuracy. They can be designed using computer-based testing methodology with a lot of different sponsorship. Department of Defense, Food and Drug Administration, and pharmaceutical industry.

This is showing you basically a screen of somebody taking the cog screen test. They are not going to use a keyboard. We basically keep them up on the screen using a light pen. You may test a whole room full of people all at one time. This is a test item for you to practice, memorize that, which one's the same, left or right. Hopefully you choose right.

This would be a divided attention test that involves working memory at the top. Remember the previous number being shown in that top square, and then a tracking test where you maintain that blue square in the center of the screen. You do both of these tasks at once. It's a very good predictor, sensitive to changes and shift and that kind of thing.

The test which we find most sensitive to sedating impairing drugs are tests of vigilance, the ability to sustain attention during a boring activity. Divided attention. Your ability to perform simultaneous mental activities, like perform the tracking at the same time that you're doing some other type activity. Working memory, holding information temporarily in your mind.

This is just showing you a very simple 12-minute test. We've actually recorded this on to a Palm Pilot, and looking here at Diphenhydramine in yellow, 50 milligrams, versus placebo, basically you're looking at four times the number of lapses of attention for a subject taking a common over-the-counter sedating antihistamine.

This is a study we just did, sponsored by FDA, actually looking at very low dose over-the-counter antihistamine, Chlorpheniramine at two milligrams and four milligrams versus placebo, and this is looking seven hours post-dosing. Nobody's reporting any sleepiness. Stanford Sleepiness Scale scores all below two, yet there is impairment on our dual task tracking test for the subjects at either dose in the absence of feeling sleepy.

Summarizing for you. Sedating medications can cause impairment in the absence of sleepiness. Sedating effects may carry over to the following day, even when the medications are taken the night before, and the functions which we believe are most vulnerable to sedating medications, which we've demonstrated, are in fact vigilance, very important in transportation safety.

Psychomotor skills under divided attention obviously involved in transportation and working memory. We have, we can provide reliable and valid measures. They are available. We're evaluating all of these dimensions of sedation, self-report, physiological and performance.

Thank you very much.

DR. ELLINGSTAD: Thank you, Dr. Kay.

Our next panelist is Dr. Bert Spilker, Vice President of the Pharmaceutical Research and Manufacturers of America here in Washington, D.C.

Dr. Spilker?

DR. SPILKER: Good morning.

I'm Dr. Bert Spilker, Senior Vice President of Scientific Regulatory Affairs for the Pharmaceutical Research and Manufacturers of America.

PhRMA represents the country's leading research-based pharmaceutical and biotechnology companies. In regard to the subject of this panel's discussion, I wish to make seven points.

First. Every investigational drug is carefully and thoroughly evaluated for adverse reactions it may cause.

Second. These evaluations are conducted in both artificial as well as highly-controlled clinical trial settings during Phase I and II of development of a drug, and, in addition, in close to real world clinical settings during the Phase III development.

Three. Evaluations are made through adverse drug reporting via spontaneously-volunteered verbal communication by patients in diaries recorded by patients when they're kept as part of a trial and in responses by patients to written questionnaires for quality-of-life and for other tests.

Responses to verbal non-biased questioning, such as, have you had any problems or noticed anything different since you were here last, are the basis for collecting adverse drug reactions during each phase of drug development.

Four. Any real world or real life events, such as traffic accidents during a clinical trial, is collected as an adverse event, no matter how mild, and every attempt is made to ascertain the cause, whether it be drug-related or non-drug-related; i.e., the accident could be due to drowsiness due to the drug or from an event due to the disease under evaluation or from other non-drug-related causes prior to the accident.

Five. Adverse drug reactions for an investigational drug are compared against placebo and often versus other approved drugs prescribed for the same disease, either in head-to-head clinical trials or using data from the respective package inserts.

A benefit-risk determination is eventually made by the sponsoring company and by the FDA, and drugs are allowed on the market if their benefits exceed their risks.

Six. After market approval, adverse drug events that a company learns about through its post-marketing surveillance program or global safety network, as described in the Code of Federal Regulations, are sent to FDA on an expedited or periodic basis. The company's network captures reported ADRs occurring anywhere in the world.

Seven. The relationship between drowsiness as an adverse drug reaction and impairment of performance has not always been demonstrated to be related or correlated. Drowsiness tends to be a subjective feeling, whereas impairment is based on more objective testing.

Various methodologies have been utilized to evaluate performance impairment in both real life and clinical trial situations when certain adverse drug reactions, such as drowsiness, have been associated with its use in some patients.

There are more than a dozen commonly-used tests that measure performance impairment. However, there is no accepted universal standard approved by FDA for testing impairment in a clinical trial setting, and a validated reference for what may be a clinically meaningful threshold of impairment is not presently agreed.

In conclusion, well-documented methodologies are currently being utilized during the development phases of a drug for evaluating adverse drug reactions and their potential relationship to performance impairment.

Once a drug is approved for marketing, the drug's safety profile continues to be monitored through post-marketing surveillance programs with resultant relevant updating of prescribing information based on the additional information.

Thank you for the opportunity to address this group, and copies of my talk are available in the table outside.

DR. ELLINGSTAD: Thank you, Dr. Spilker.

Our final witness on this panel is Dr. William Soller, Vice President and Director of Science and Technology for the Consumer Healthcare Products Association.

Dr. Soller?

DR. SOLLER: Could I have the slide, please?

Thank you, Dr. Ellingstad, Dr. Galson. Good morning, and thank you for the opportunity to be here.

I'm Dr. Bill Soller with the Consumer Healthcare Products Association, a 120-year-old trade organization representing the manufacturers and distributors of non-prescription medicines and dietary supplements.

Do I ask you for the next slide? It didn't seem to be working. I think I'll do it orally, if I may.

My remarks focus on OTC antihistamines, a class of OTCs with a drowsiness side effect. OTC antihistamines are highly effective for treating symptoms of allergies, runny noses and sneezing associated with the common cold, for nausea, and for some ingredients as sleep aids.

OTC antihistamines have been thoroughly evaluated under the OTC review by FDA and its expert advisory panels, including a detailed examination of the chief side effect, drowsiness, the concern about driving and operating machinery, and the creation of special warnings for this side effect.

FDA and its panels concluded that there is a wide range of susceptibility to the drowsiness effect with less than 10 percent to up to 50 percent of users experiencing drowsiness, depending on the antihistamine used, the dose and the underlying condition.

FDA and its panels also created specific carefully-worded drowsiness warnings for different classes of antihistamines, depending on the degree of drowsiness associated with their use. In so doing, they created in detail or they considered in detail the potential for machinery-related accidents and the potential exacerbating drug interactions.

With this warning and other labeling, OTC antihistamines have been determined to be generally recognized as safe and effective.

Next slide. Antihistamine containing OTC products bear a specific drowsiness warning shown here. Though drowsiness may occur, it does not always occur in all users. Alcohol and drug interactions are identified, and there's a specific caution about motor vehicle and machinery operation, and I might add, studies support the fact that consumers read the label before using the product the first time, and CHPA has had a very long involvement in educating consumers on the need to read and heed the OTC label.

Next slide. We conducted a 10-year post-marketing surveillance analysis for these OTC antihistamines in single and combination products, looking at AERs with an accident-related term in persons 16 years or older. The accident term was defined very broadly to include all forms of transportation accidents and other possible related terms, including falls, injured limbs, and so on.

Next slide. Over this 10-year period, there were a total of 23 serious AERs with antihistamines as a primary or suspect -- secondary suspect drug with an accident term in any field of the AER. There were no more than four AERs in any one year over this period.

About 850 million OTC units for adults alone were sold during this 10-year span, and I might add there are also RX uses for certain of the drugs studied. These findings were supported by previous studies by the National Highway Traffic Safety Administration, Ray et al., and Turnbridge.

In a study in the early '90s by the National Highway Traffic Safety Administration, post-mortem blood samples were analyzed from over 1,800 drivers in seven states. NHTSA concluded this and other studies have found that there are relatively few drugs which have prevalence large enough to present a highway safety problem. These were mainly drugs of abuse.

Ray et al. determined the risks for injurious crashes for drivers who had received prescriptions for various drugs, including prescription and crash records, for over 16,000 elderly drivers in Tennessee. However, the relative risk for current users of only RX antihistamines was 1.2 with the confidence limits spanning one, and no dose effect was demonstrable.

We therefore in these long-term larger-scale epidemiologic studies see no signal for concern. We conclude that the OTC warning label and educational programs are having an impact.

May I have the next slide, please? With the new drug facts label, there will be even better communication with the consumer. On the left is the old label. On the right is the drug facts label. Note the more consumer-friendly format that allows a more prominent and more consistent placement of the drowsiness label across the product categories.

You may not be able to read it from the audience, but the warning appears when using this product, marked drowsiness may occur and so on, in the middle of the label.

May I have the next slide, please? In conclusion, OTC antihistamines have a demonstrated history of safe and effective use when used according to label directions. OTC antihistamines are appropriately and adequately labeled. Drug facts label will make the warning label even better.

CHPA believes that it's important to maintain an on-going program of consumer education on the importance of reading the entire OTC label.

Thank you.

DR. ELLINGSTAD: Thank you, Dr. Soller, and thank you to the panel.

What we'll do now is turn to our Technical Panel for a round of questioning. I'd again like to remind the people in the audience that if they have questions that they would like asked of this panel, please identify the staff that are roaming around and obtain from them a card, write your question down and hand it to them, and they'll bring it up here, and we will ask those questions.

I'd also like to remind the party groups to think about their questions and to identify their spokesperson here, and we will, after the Tech Panel is done with their questioning, begin a round of questions from the parties.

To lead off the Technical Panel questions, Dr. Garber will start.

Questions from Technical Panel/Parties and Discussion

DR. GARBER: Thank you. Thank you very much, Dr. Ellingstad, and thank you very much to the panel. I really appreciate your presentations.

I do know that we had a little bit of audio-visual difficulty with Dr. Weiler's presentation with his videotape. Has the video tape problem been corrected? Can we show that video tape now? I just wanted to give Dr. Weiler an opportunity to present that, if in fact that's -- we have that ability now.

DR. WEILER: I believe we can certainly show it. I believe we can show it now. I guess it's coming from the booth as opposed to from down here.

(Video tape shown)

DR. WEILER: This is an animation of the National Advanced Driving Simulator, and it demonstrates the X, Y, and you can't see the Z access. You'll see that when we zoom in on it.

But it's a facility that exists in the Oakdale Campus at the University of Iowa, and here we see zooming in on the facility itself. This is the control room that runs the facility. You can see off in the bay the dome structure that contains the cab.

We have currently four cabs that we can use in that dome structure, two sedans, a tractor-trailer front end and an SUV.

This is all animation demonstrating driving maneuvers. There's 360 degree of visuals, something very unique. Here, we see the actuators, and this is what gives us the feeling of motion. It's very realistic. So, we can set crash scenarios that really wouldn't be possible with on-the-road driving.

This is a demonstration of a spin-out. This is what the subject would actually see while driving the car. Both the sound and the feel are very realistic, and we can record all of the end points that I showed on the slide. It can help us to understand what happens.

We have in-town driving. We can pick tiles to set these up very rapidly, so that you can have a scenario that's in town and quickly goes to a rural setting. We can repeat these drives with every individual. We have triggers on the roads, so that when you drive over a trigger, it may cause something to happen, such as somebody jumping out in front of the car.

It's extremely easy to set this up, and we have data reduction tools that allow us to collect the data and analyze them quite rapidly. It is an $80 million facility, so it's not something that we can do for every drug and every test, but it does allow us some tremendous flexibility in being able to run studies in ways that really weren't possible in the past.

Thank you.

DR. GARBER: Thank you very much.

I just have actually just one question, a quick question, for the entire panel, and I'd like to get an answer from each of the participants, if I may, so that we can quickly get this to the parties after our FDA counterparts have also asked their questions.

But the only question I have, and this is for each of the members, is, do we have the capability now, given the tests and the data that we have available, do we have the capacity to identify drugs which we do know do not impair vehicle operators?

In other words, can we reliably identify or compile a list of drugs which we now know or which we can readily identify fairly shortly that do not in fact impair vehicle operators that we can declare relatively safe for their use?

I'd like to pose that to each of the panelists.

DR. WEILER: There probably are a group of drugs that have been studied to some extent. The problem is that I believe that the drugs that don't cause drowsiness to any great measure probably haven't been studied very well for their impairing capacity.

So, if we believe, as we've shown with the antihistamine classes and with other drugs, that drowsiness and the subjective feelings don't predict impairment, the problem is the drugs that are either mildly or not very sedating at all have really not been studied in any great way for impairment.

So, we can make guesses, but I'm not sure that it would be entirely accepted by everyone.

DR. O'HANLON: I disagree with my colleague. I think we know a number of drugs which are not impairing, relatively, of course. There can always be an impaired -- one impaired person out of a thousand or whatever, but in the -- for the drugs that I would call non-impairing, they have no significant effect at the recommended dose, no significant effect at twice the recommended dose and sometimes higher, up to four times, and there is no individual in a representative group of, say, 24 to 32 who shows an anomalous untoward reaction.

Now, having said that, the caveat I have to add is that in our tests in the Netherlands, we did not study every population of drivers, and what I'm saying now pertains to young either patients or volunteers and not elderly patients or otherwise impaired drivers.

So, with those caveats, yes, we have a number of drugs in every therapeutic class, that we have nearly every one that we've defined as safe.

DR. KAY: The only thing I would add would be that if we used as a criteria lack of evidence of sedation meaning no findings on self-reported sleepiness, no findings of problems or abnormalities on physiological tests of sedation or performance measures, we have very few drugs we've tested across all those, you know, types of measurement.

That was in fact a lot of the work being done in the Department of Defense when we were doing work on chemical defense drugs and looking to find out which drugs you could take and still fly a plane, which drugs you could take and still drive a tank, and we did study certain medications but very few have been studied across all of those domains and dimensions of testing.

DR. SPILKER: It's well known that people react quite differently to any drug, and it's difficult, if not impossible, to say that Drug X never causes drowsiness.

If you look in the PDR, you will see that many, many drugs not associated with sedation and impairment certainly also have drowsiness listed as an adverse reaction.

So, I think it would be a disservice to say to any group these are drugs that do not cause drowsiness or sedation. I think we'd be sending the wrong signal medically.

DR. GARBER: Just as a follow-up question to that then, you're suggesting that all drugs may potentially cause sedation or drowsiness? Is that my understanding?

DR. SPILKER: Yes.

DR. SOLLER: Thank you.

You know, I think it's important to think about how far we want to tease out some of the laboratory values and how far we're going to look at those laboratory studies.

Dr. Galson, Dr. Ellingstad, do we have anything we need to do now? I'm happy to return to my answer later, if I need to.

DR. ELLINGSTAD: This is Wednesday, and they do test the fire alarms. I'll ask our staff to verify that that's what it is, and we'll --

DR. SOLLER: Okay. We'll see how well we do on divided attention.

DR. ELLINGSTAD: -- deal with it. Thank you.

DR. SOLLER: I think it's important that we think about how far we want to tease out the laboratory values and particularly as we look at simulator or other types of studies, where what we see are perhaps doses that are not those that are necessarily used in an in-use situation.

I'm speaking from an OTC context in certain cases. Our view is that the broad term sedation as has been defined in the clinic and the clinical studies has been appropriately looked at for OTC medications. This is well studied through the OTC review.

There was a great discussion on the issue of drowsiness and the effect on driving as well as operating machinery for certain of the products and even beyond the antihistamines, and when you look at an RX/OTC switch drug, again a very thorough clinical experience, and I think in the end, when you match that against what we're seeing in the AER profiles as well as the larger epidemiologic studies, I think we're on track in focusing our efforts on the kinds of warnings that would direct people about what products might cause drowsiness or impairment.

DR. GARBER: Then your colleague suggested that all those drugs might cause impairment. Are you in agreement with that?

DR. SOLLER: No, I'm not in agreement with that.

DR. GARBER: Okay. Thank you.

DR. SOLLER: Although I will say, you know, I'm talking about recommended dosages for OTCs in that context.

DR. GARBER: Understood. I'd like to pass the questioning now to Dr. Temple for the FDA.

DR. TEMPLE: Is this on? Yes. A number of you have been talking around this.

Do we have enough information to think that any one of these kinds of tests provides different information? For example, Dr. O'Hanlon has developed one specific test for driving based on lateral movement. Dr. Weiler has shown a method for assessing a wide variety of functions, and Dr. Kay has talked about a variety of things that tell how alert you are and whether you fall asleep when you lie down during the day.

Are all these -- do we have any way of knowing whether all of these things tell us the same thing or whether they're actually different? Are you just as informed if you know that a person is not alert on one of the standard tests as you are if you have information about lateral motion?

Is there any way to tease this out? Obviously my question goes to whether we should be thinking of a standard battery of tests or whether, as we have sort of concluded in the past, that once you know a drug is sedating, it causes all of these problems, and you just already know that and the rest doesn't add much.

Can any of you comment on that?

DR. KAY: From perspective neuropsychology, I would say that it's important that we study not just one test as an indicator of whether there is sedation because we look at medications. Some medications will affect psychomotor functions, skilled motor activity and have very little effect, if any, on cognition.

For example, if you look after days of dosing with some of these medications, we cease to see the effects on measures of attention, concentration, vigilance, but we can still detect significant effects in psychomotor ability, especially under divided attention.

So that, I think it's important that we realize that different drugs are going to affect the brain differently. We're talking about central nervous system function and differential effects of different agents depending upon what neurotransmitter systems are being disrupted by that particular medication.

DR. O'HANLON: An investigator uses the tools at his disposal. I don't have an $80 million simulator. On the other hand, I did work in a country that allowed me to test drug effects in a real environment which would be difficult in the United States, but it could be done. As a matter of fact, it started here.

What you have, though, is a consensus across people who devote full time to assessing the behavioral toxicity of drugs regarding some drugs, and there is a gray area where various investigators will argue with each other about whether this drug belongs in the next category or the next category down, and then we go into a white area where nearly all investigators agree that the drug is relatively safe.

In spite of the diversity of methods, experience with these drugs in performance testing laboratories has led to a very broad and very strong consensus about the worst and the best drugs. I don't think that the diversity of methods is the issue.

Everybody uses what they have to, but the conclusion, the focusing, the narrowing of opinion on certain drugs is inescapable. It was there 15 years or 17 years ago, Bob, when I visited. It's there, and it's better today.

DR. TEMPLE: But that, in some ways, is what I'm getting at. Should we be content if any one of these methods, even if it's -- whether it's an actual driving method or it doesn't involve driving, shows impairment, do we then more or less have our answer, assuming we've got data over time and data related to dose and all that, or do you actually need a driving test?

DR. O'HANLON: Impairment is not a real -- something in itself. I mean, drugs can be impairing. You can have such a sensitive test that you can measure tiny impairments of minuscule amounts of dose of drugs relative to therapeutic doses. That's not important.

You need an external standard. We've tried to use the blood alcohol concentrations as our external standard of safety. It may or may not be the best. You need that, and if you have that, you can -- impairment is not the issue. It's impairment relative to a drug which is known to be behaviorally toxic and known to kill people at a rate of 40,000 a year in the United States. If you have that, you have a very good screening test.

DR. WEILER: I'd like to make one point. This raises a very -- I think, a very important issue, and that is, that it's very clear why drowsiness has been something that we've been able to quantify and put into package labels, because we can measure it, and it's pretty clear what we're measuring. It doesn't matter whether it's a visual analog scale or collecting adverse events or whatever we're doing. We can measure drowsiness.

We've gotten into a very difficult area when we talk about measuring impairment because there are so many different tests, and there are so many different standards.

I mentioned that driving is a real world task, but it's not the only real world task. The person who operates heavy machinery, the person who works in a shop and has to operate equipment there, those are also very real world tasks for those people, and the issue's going to come up in developing some kind of a standard, some kind of a way that we can quantify the impairment that people will accept.

I agree that it shouldn't be one test, but there should be a group of tests or a group of standards by which we can determine impairment, and it shouldn't just be drowsiness. We shouldn't just say that the lack of drowsiness is okay, you're fine, or if you're drowsy, that we don't have to go further in quantifying the level of impairment, and that's going to be the difficult task.

I don't think we're going to come up with a single test today. I think that's going to be a task that you folks are going to have to work with and some time come down with a series of tests that will be acceptable, that will work, that will allow investigators to be able to look at the question and know what kind of guidance they need to determine where they're going to go next in looking at the impairment of these various drugs.

DR. SOLLER: Just a comment, if I could. Thank you, Dr. Temple.

I think you're on target when you restated the question, do we actually need a driving test for every drug, and I don't know. Maybe the investigators would say so, and I do find the results interesting, but from the state of the knowledge that we have now, the questions about extrapolating from laboratory to in use and whether these particular studies are validated and which ones to pick, I think you're probably on target, at least where I thought you were going, in terms once we know that it's sedating, do we have enough at this particular time?

I think if you know a product produces drowsiness, then in some individuals, potentially it will affect performance, and if you find that you have ambiguous findings around that particular effect in a battery of clinical trials that are done on a new chemical entity, then maybe on a flexible case-by-case approach or perhaps that's the way to do it, to look for further performance effects that might be seen to better elucidate what's going on until we have, I think, more information.

DR. TEMPLE: This isn't a question. It's really a comment on what everybody said, but one of the things that was very striking to me was the pretty precise ability to see how long impairment lasted with some of these tests, which is obviously crucial, Bill.

You know, you can put watch out for drowsiness on your label, but that doesn't tell you about dose. It doesn't tell you about duration. It's really not enough information, given what we've just seen. There are big differences in how long the effect lasts, you know.

Sonata wipes you out for the first four hours and then nothing. That's different from the other drugs. Those seem very important.

DR. SOLLER: Well, I haven't seen that one on the switch list, but if I could comment, it's important to think about, and I'm again talking from an OTC standpoint, not for prescription products, but to think about what does go on the label, and what is transferrable to the consumer, and what they can act on, and at least from looking at the information we have at hand, we're not seeing that signal that would suggest that what has been done by FDA and what is now being done with the new drug facts label, and I can say that most of the antihistamine products are already in that label and all will be there by May 16th, 2002, the compliance date.

So, we're in the process of a very large change in information that's going to be conveyed to the consumer on what is already apparently a very good AER profile for these products.

DR. SPILKER: I wanted to clarify my response briefly to Dr. Garber's question before.

I was saying that drowsiness or sedation is likely to be reported by at least some patients for all drugs, not that this is considered or the drug is considered as impairing or as clinically significant.

But when you do clinical trials or you collect adverse reactions, you will always find reports that some patients are sedated or drowsy.

DR. GARBER: Thank you for that clarification. If I can follow up just briefly again, as we've heard other people state here, are you suggesting that that subjective report of that adverse event may not be a good indicator of whether the drug is impairing for the purposes that we've been discussing today?

DR. SPILKER: Yes, I would certainly feel that.

DR. GARBER: Okay. Thank you.

DR. TEMPLE: But, I mean, we know that all so-called non-sedating antihistamines have reports of drowsiness, but they're equal to the reports of drowsiness in the placebo group.

So, we conclude they're minimally impairing. You don't mean everybody's going to report drowsiness from time to time? So, you don't mean that has anything to do with the real effect? You wouldn't really know that.

DR. SPILKER: Well, I agree with you. I'm just commenting on the fact that you will see these data, and then we interpret it the way you do.

DR. WEILER: Could I make one more comment? The issue about quantifying the impairment is important or otherwise we'd trivialize the warnings. If we put a warning on every antihistamine that it's impairing, we then send a message that it doesn't matter what you take, and so the really impairing drugs are drugs that people are going to take just as commonly as those that are either minimally or non-impairing at all. So, it is important to quantify the risk in some way, if we can.

DR. SWEENEY: I have a question for Dr. Weiler. Have you used the driving simulator to test the effects of any specific over-the-counter drugs, and can you describe the results?

DR. WEILER: Well, we have used it in a study that we looked at diphenhydramine, and we compared it to alcohol. I could review some of those data, if you'd like to, very briefly.

DR. SWEENEY: Please.

DR. WEILER: Okay. Do we have our AV person here to --

DR. SWEENEY: Anyone for AV help up front, please.

DR. WEILER: Try to go through this very rapidly. We do have some data on the point. We looked at the Iowa Driving Simulator which was slightly different than the new National Advanced Driving Simulator in that it doesn't have a track. It is a motion base, but it doesn't move on a track.

This was a simulated driving. There were two phases. The first phase was about 30 percent of the drive, and it's following a car. The second phase is going through a variety of curves and driving as a free agent as you typically would.

Next. We looked at coherence as the primary end point, and on this slide is an example of the worst, the best and the median coherence. Is there a pointer on this thing? The big button. You'll just have to read worst, median and best, and the bottom one is the best. It shows really close following, and it happens to be in somebody who was drunk.

Next slide. And the point is that someone who is drunk can follow very closely, but that's the only test they can perform well, and in this particular case, we found significant differences between fexophenidine and diphenhydramine, alcohol and diphenhydramine, and placebo and diphenhydramine, and in fact, in this particular end point, the diphenhydramine group performed the worst.

This was a divided attention task. They did well. The alcohol group did well at performing this task but nothing else very well, and the alcohol was .1. They were dosed to .1. I'm not moving this thing, am I? Oh, okay.

This is minimum following distance, and it shows significant differences between the fexophenadine and alcohol and placebo and alcohol. Now, we're starting to see the alcohol group not perform very well.

Steering instability is something we can measure very easily in the facility. We found differences between diphenhydramine and fexophenadine, diphenhydramine and placebo. I won't go through the other groups because I really think the issue here is the impairment that we saw with the diphenhydramine.

Steering instability in the phase where they drove as a free agent, we saw the same kind of results. Again diphenhydramine impaired and caused steering instability. There were left lane excursions and that's important obviously because you won't want to be driving in the lane where oncoming traffic is coming, and this gave us an opportunity to look at that, and again you can see the diphenhydramine group stands out with differences between it and the fexophenadine and differences with the placebo group.

We looked at self-reported drowsiness, and as expected, the diphenhydramine group had the highest percent of self-reported drowsiness, but, and I think this is probably one of the messages that came through very loud and clear, is we've got really nice P values looking at the correlation between drowsiness and performance impairment.

We've got P values that are fine. Those are in the parentheses, but when you start looking at the R values, which are really more important, the correlation, we get very poor correlation. It's highly significant for a very small percentage of the population. That's really a problem because the people who thought they were drowsy and wouldn't drive, the cues weren't there, and in fact, I don't know how well this projects, but if you look at the very drowsy drivers, they aren't the ones that had the accidents. The accidents are in red, and there's one in black that are -- I'm sorry -- the black is the median.

They're in red, and they demonstrate where the crashes were in a scenario that we set up, and we didn't see crashes necessarily in the most drowsy individuals. We did see crashes in those who had the high crossing counts, so that those people who drove into the left lane were more likely to have a crash in this last event. So, that's a really concerning result.

I'd be happy to show some video clips if you want. I've got a two-minute video. It's up to you, if you want to see it. Yes? Okay. We'll do our best here. This is certainly multimedia time.

(Video tape shown)

DR. WEILER: We're showing the Iowa Driving Simulator. This is a control room in that old facility. The way we take somebody up to the facility is they walk up the ramp, and you can see the dome structure. This is getting in the car. This is very similar to what NADS is, a regular car, seatbelt, adjusting the mirror. Again, the control room controls the way the car drives, and this is what you would see if you're sitting in the driver's seat.

It doesn't -- it isn't easy for me to see here. I hope you can see where you all are sitting. Again, there's a side mirror rearview. We had 270 degrees of visuals, and you can see the motion. It was very realistic, again very similar to NADS, it just doesn't move on a track.

You'll see four panels, a driver right there. Let's see. You can see steering instability. We can measure that, and we can view it. Here's the center insert that shows the speed. We see where the foot is. Acceleration and braking are recorded and that's a view of the bay itself showing frame counts.

Here, we're looking at the ability of the car to follow. Individuals who were on placebo were able to follow the car at a comfortable distance. In this case again, a person showing steering stability. She's able to drive real well and follow the car, does a nice job.

I don't know if this is going to demonstrate it, but we were able to measure the distance, and the varying distance was tremendous in the people who were on diphenhydramine. Here, we see an example of alcohol driving over the center lane.

Now, this is the last event where I talked about crashes. It shows the person crashing. These aren't things we'd want to be doing in the real world, and we can measure those. I mean, we can actually measure the fact that that individual ran into that tractor-trailer coming at him, and we were able to look at those.

This study wasn't powered for that, but it does allow us to do that in future studies. We can do either frequent events or we can do infrequent events to measure these kinds of things.

DR. TEMPLE: When he crashed, did he fall asleep briefly? Is that what the assumption is?

DR. WEILER: Yes. In that particular individual, he was having a lot of problems getting around, and he did hit the oncoming vehicle.

What was supposed to happen was that they had driven this scenario three times previously. It's a 45-to 50-minute drive, and they're pretty well lulled to sleep at the end of the drive. We're at the end of the drive for the fourth time, and so it wasn't powered for this particular event, but we wanted to throw it in and see what would happen if a car pulled out that had been sitting in the driveway every one of the three previous drives, and so it pulled out, and we measured the time, we can measure reaction time, from the time it begins to move until the time it's blocking the lane.

What's supposed to happen is the car blocks the lane, plus there's a vehicle coming in the other lane. You've got some choices here, and the best one is to stop, and the people would stop generally, but some people would go into the far lane.

We had one woman who was so drunk that she was in the far lane to begin with and actually got able to get back to the right lane before the tractor-trailer came. So, we have a variety of different things, but that scenario is set up. It's an identical scenario for everybody. We can run them through it. We can categorize the events.

It allows us to do some really tremendous things that are very well controlled, like we would like to do in a science laboratory, where we can actually look at events and control for everybody passing through the study. It's wonderful the way we can look at these kind of things in that setting.

DR. TEMPLE: This, I'm sure, is going to seem like a naive question. Are you trying to find out whether people are in a state where they're likely to actually fall asleep and therefore run into something or is their function impaired even if they're not asleep or both?

DR. WEILER: Well, our interest was really looking at the end points that were important and not -- sleepiness and drowsiness, if the person can stay awake and drive well, is fine, and that was my contention on one of the early slides, was that if you're drowsy, but you're driving okay, it's not a pleasant feeling, but that's not really what this is about.

What this is about is the individual who's impaired. Our end points that we're most interested in are those that reflect impairment, inability to control the car, inability to keep yourself in your lane, keeping the lateral position where it should be. You pick the lane of best fit and stay there, so you're not over-controlling, a lot of steering instability. We don't want that because we know that predicts a bad event, a crash or some bad event occurring.

We looked at drowsiness. We looked at questions of do you feel impaired to predict those kinds of things because we thought that was important. We find a tremendous disconnect, as the literature demonstrates, but our interest was in impairing. What was impairment?

DR. TEMPLE: But Dr. Kay showed data that people had way decreased sleep latency, even if they did not feel impaired. So, whether you're going to fall asleep or might not relate to whether you feel drowsy.

DR. WEILER: That's correct. That's why we feel it's important to cross correlate, and you may say cross validate, these various tests against each other. I believe that's very important, so that we understand the consequences of changes in the mean sleep latency and some of the other tests that would predict impairment.

But we have a real world task. We can either do it with on-the-road driving, things that we've done, or we can do it in a simulator. Again, we think there's some advantages. In some cases, there are advantages of real world driving in a real car, and in other cases for the simulator, but the point is it's a real world task, to which we can correlate some of those other tests, low fidelity, low in simulators, and some of the other cognitive tests and some of the other tests that were described, allow us to run the continuum from a facility that's really the high end to the studies that are obviously a lot less expensive to perform, but we can cross validate each other against the other tests, so we can look at how they predict the impairment in a real world task, driving.

DR. SOLLER: I'd like to -- can I make a comment just by way of putting that in perspective? Because I think that study was, as I saw it reported out, had dramatic headlines about the comparison of alcohol to the OTC in question, and just by way of perspective, from the prevalence studies, I'm remembering that the fatal traffic accidents related to alcohol were upwards of 50 percent or more, and I think one of the questions you have to ask is that if it translates out from a simulator study that alcohol is worse than a particular drug, you have to ask where are the crashes, particularly given the very large usage profile for some OTCs in this regard or other drugs.

It's possible that one of three things is happening. The in use antihistamine drowsiness is not happening as much as we think. There's individual variability, 10 to 15 percent, depending upon the dose, the drug, the condition. When it does or if consumers think that it may because they read the label, they can compensate. They might not choose to drive. They might chose to stay home in bed with their particular malady or third, the simulator studies may have some limits in terms of how you extrapolate that out to real world.

The other comment I wanted to make is that just by way of putting this in perspective, often the 50 milligram dose is the one that is chosen in these particular studies, and from the standpoint of usage patterns, only a minority of the number of different antihistamine-containing products recommend only the maximum dose for this type of antihistamine, the 50 milligram dose.

They're usually recommended in the context of a 25 to 50 milligram dose for diphenhydramine, and many products only have the 25. The expert advisory panel and FDA in the final monograph recognized that consumers would choose these products based on labeling and based on their experience.

The so-called PM products or the night-time products have 50 milligrams as the recommended dose but with directions to take at bedtime, and I think this is important as we think about the range of drowsiness, this 10 to 50 percent that we see for this class of drugs, the dose, the underlying condition, the fact that concomitant medications are taken in combination like a sympathomimetic, because there is extensive variability.

So, in sum, I think you need to take into account usage patterns when trying to understand the practical relevance of simulator studies and also recognize that the consumer's being informed that a market, a very significant effect, market drowsiness, may occur with the product, and in a separate part of that warning, being warned to use caution about driving a car or operating machinery.

That, with what has been very extensive publication -- public education on read the label, I think, can be supportive of what we're seeing in the post-marketing surveillance studies and the other prevalence studies.

DR. KATZ: I have a question about time course of effect. We've seen some information about the time course post-single dose, but what about post-multiple dose or drugs to be given chronically? Is there an accommodation to this effect over time?

DR. O'HANLON: Russell, are you asking me?

DR. KATZ: Anyone who knows.

DR. O'HANLON: Okay. Those figures that I showed were generally the second night of use. We have done some chronic dosing with hypnotics as well as with most other CNS active medication that we've studied.

There generally is the phenomenon of tolerance, as you'd recognize. On the other hand, there is also the phenomenon of accumulation. Dalmane's effects increase for a week as with accumulation and then begin to decline afterwards with developing tolerance.

As another example, using Ativan, two milligram BID, which is a pretty hefty clinical dose, with anxious patients, we found out that the patients drove very badly the first day indeed and felt very -- sedated is not a good word. They just felt bad. They felt sleepy. They felt ataxical, all kinds of things. By the end of a week, they were still driving bad, but they felt much better.

There was a decline in impairment over the week. There was a greater decline in subjective drowsiness, and the decline was about the same as the accidents and the number of injured, including fatally-injured drivers, in Saskatchewan as a function of time from the initial prescription.

There is a drop in the relative risk, taking Lorazepam, from 13 times normal in a first week all the way down to two times normal at the end of a month. That's the kind of pattern we were seeing. Yes, tolerance does occur. Yes, you are still in danger of a fatal accident at the end of a month in spite of tolerance occurring.

DR. WEILER: I certainly agree that these studies need to be conducted after first dose and at steady state, but one of the things that we ought to recognize is compliance is a terrible issue with drugs that we prescribe, and many of these antihistamines are really taken on a PRN basis.

So, if we actually look at the use of the drugs, we tell somebody to take the drug when they're supposed to take it, and they really don't take it that way, they take it now, and then they don't take it tomorrow or the next day, they take it the day after.

It makes it very difficult to look at impairment. So, I think you can't just look at steady state. You really do have to look at the effects after a first dose or acute intermittent use.

DR. KAY: When we've looked at steady state, what we have found is that you need to think again in terms of these different dimensions of sedation.

With respect to self-report, we have found, for example, with diphenhydramine, that 25 milligram QID dosing, people continued to show significant fatigue with five days of that steady state dosing on self-report measures. So, that would be looking at self-report. A recent study looking at Citerazine, showing significant self-report sedation at seven days of dosing. So, self-report seems to persist.

With respect to the physiological measures, we see tolerance, clearly, in our sleep latency testing that we do. If we continue night-time dosing with Chlorpheniramine for four nights, by the fourth night, the eight milligram dose was pretty much close to the 10-minute mark. There had been quite a reduction in the day-time sleepiness.

The higher dose, the 12 milligram, was still at about eight-minutes sleep latency, which is clinically abnormal. So, there is evidence physiologically of tolerance.

In terms of the cognitive tests, those seemed to develop some kind of -- I don't want to call it tolerance but more adaptation. You learned to function under the influence, and we began to see the dropping out of the cognitive effects after about three days of continued dosing, even, you know, with several of these medications.

But with respect to psychomotor, that's why we can't just rely on any one measure, we have shown, for example, at the 25 milligram diphenhydramine dose on that tracking test I showed you, 15 percent of the subjects on diphenhydramine crashed on Day 5 compared to zero percent on placebo on that kind of measure.

So, psychomotor performance can persist, and I think John or Jim might be aware of some research done in the Netherlands by the military looking at three weeks of antihistamine dosing and again showing on their dual tasking test a persistent psychomotor effect, but the self-report effect was dropping down, and the other cognitive effects had disappeared.

DR. ELLINGSTAD: I might interrupt. I think we've reached a point where we probably could use our first break of the conference. I'd ask everyone again to develop their questions and the audience to submit them on the note cards, and the parties to be assembling theirs.

We will reconvene at 10:15.

(Whereupon, a recess was taken.)

DR. ELLINGSTAD: A couple of things before we begin. There's apparently been some confusion about where to get cards. So, I'd ask the staff who have cards to distribute to collect questions to make themselves known and wave your cards around.

DR. GALSON: The card ladies are back there waving the cards.

DR. ELLINGSTAD: So, anybody that needs those, you know, please summon them and turn in your questions. We have at the moment one individual who has indicated that they will be making an audience presentation. That's in your agenda at 11:15.

Anybody else that falls into that category, please check at the desk outside, and we would need to have them registered immediately before that would happen.

Okay. We will resume, and before I turn it back to the Technical Panel, let me exercise the prerogative of the chair and sneak in a question here.

It was interesting, the discussion, I guess, that started with Dr. O'Hanlon, that referred indices of impairment to alcohol, and what I'd like to ask as sort of a general discussion of that as a calibration standard for impairment, you know, from other kinds of agents, and my assumption is that you're going on the basis of a long history of epidemiological research that associates various levels of blood alcohol with known probabilities of accident involvement, etc., and then makes the logical extension that from that, we can use that as a calibrating standard for impairment and other drugs.

Would you comment, if I've mischaracterized that logic?

DR. O'HANLON: Thank you, Mr. Chairman. I'm glad to have this opportunity to expand a little bit on my five-minute presentation.

I used alcohol as a standard in two ways. When I compared the epidemiological data, the limited epidemiological data concerning three hypnotics, I was comparing it to the Borgenstein, the famous Borgenstein epidemiological relationship between blood alcohol concentration and the risk of an injurious or actually in this case fatal accident.

When I was referring to the empirical data from our tests in the Netherlands, I was making the comparison to data we had collected in a special calibration study. Alcohol was probably the most dangerous drug we ever studied, and we did not do that particular investigation on the real road in traffic as we did subsequently with every medicinal drug.

Rather, with the help of the Dutch Province of Ronaken and the traffic enforcement, the law enforcement personnel, we closed a 15-mile segment of secondary highway, and we took a group of 24 social drinkers defined by sociologists and psychiatrists as representative of social drinkers. As close we could come to a really representative group were civil servants, and we had 24 civil servants who undertook the test sober and at .03 blood alcohol concentration, .06, .09, 1.12, and we were very pleased to see that our primary outcome variable standard deviation of lateral position increased exponentially with the blood alcohol concentration.

The correlation between mean concentration and mean SDLP change was .99. On the basis of that strong relationship, we developed an alcohol calibration curve which allowed us ever thereafter to state the amount of weaving and swerving that occurred after medicinal drugs relative to the equivalent blood alcohol concentration.

I think that could be done for every test and should be done. Now, alcohol is a most complex pharmacological entity. It is not the same as any other drug. So, this comparison is limited but nonetheless, it's the best we've got with the most notorious hazard to traffic safety, pharmacological hazard being alcohol.

DR. ELLINGSTAD: Okay. Thank you.

Dr. Soller?

DR. SOLLER: Just a comment, and I know we're going to be talking about the labeling tomorrow. I would ask that you perhaps bear with me because as we think about these kinds of standardizations, ultimately they potentially can have a public health intervention impact in terms of where you go, and that's where I'm coming from in this particular comment.

I think from the standpoint of looking at these kinds of relationships, and I'm not going to argue it from a scientific standpoint but that stamp, they imply sort of an all or none standard, and I think that's important in trying to think about what that might look like ultimately, and that may be appropriate from a scientific standpoint, where you're investigating these products and trying to look at comparisons in the scientific framework in a laboratory of clinical setting and that kind of framework, looking for those kinds of comparisons.

But I think from a labeling standpoint, it's totally inappropriate, and the reason I say that is that for at least the products that we are concerned with in the OTC market, there appears to be a considerable amount of individual variability, that these are effects that may occur, not necessarily occur all the time in all people, and two things can ultimately happen, and that is, for those individuals who have a pejorative view about alcohol, having something like that translated into labeling would unfairly disparage the product, and for those who are interested in abusing products might well lead them to think that they're going to get alcohol-like effects.

So, just a comment as we think about how these things might ultimately translate out.

DR. ELLINGSTAD: Okay. Thank you, and we will discuss labeling and get into the actual interpretations of --

DR. SOLLER: I understand.

DR. ELLINGSTAD: -- that later. The point of my questions to Dr. O'Hanlon was principally from a psychometric point of view, of having a reference against which -- that has been reasonably well accepted and, we presume, reasonably well empirically established as an impairing substance.

DR. KAY: Just briefly, Dr. Ellingstad. Also, blood alcohol equivalents have also been worked out for many of the cognitive and psychomotor tests.

DR. ELLINGSTAD: Okay. Thank you.

DR. KAY: Expressing the amount of impairment in something like an alcohol-type thing.

DR. ELLINGSTAD: Thank you.

Let me turn it back to the Technical Panel.

DR. GARBER: Just before we get into our last few questions, I did have a couple of comments from the audience during the break that suggested that while those of us here on the Technical Panel and the Witness Panel are certainly well aware of all of the various names by which the medications are described, some of the folks in the audience are not as well versed in pharmacology.

If there is no objection to this on the industry's behalf, I would like to ask if we can at least -- and recognizing that the trade names of these drugs are not the only names by which they are marketed, but if we can perhaps indicate what some of the common trade names may be for these medications, just so that our audience understands what we're talking about when we are discussing some of these drugs.

Is there any objection to that on --

DR. SOLLER: I thought we were here to talk about the ingredients. Very purposely, we did not include the trade names in the AER analysis that we presented because of the issues of causality and mentioning one trade name and not mentioning all, that's a certain degree of unfairness as well.

I would opt for dealing with the ingredient names.

DR. GARBER: Okay. Then I'll have to ask that if we can at least describe what the drugs are commonly used for, unless there is an objection to that on behalf of the industry.

DR. SOLLER: Oh, I think that's fine. In fact, I mentioned for antihistamines, they are used in cough/cold preparations, for runny nose, sneezing, for cough. They're used -- some of them are used as sleep aids. Some are used as anti-nausea medications and others for -- and all of them for allergy symptoms, by way of examples.

DR. GARBER: Okay. And I'd like to -- if we can, when we do discuss a drug or if it's something that we haven't mentioned in awhile, if we can make that same -- if the presenter can make that same comment, just to note what we're talking about for those of us who are not all that familiar with the medications and their uses.

Thank you. We have, I think, one or two more questions from the rest of the Technical Panel.

DR. TEMPLE: Much of the data on impairment was presented as changing meanings. Do any of these studies allow one to determine whether what you're seeing is a fairly consistent change in the entire group or a particular subset of a population that is driving?

In other words, how much individual data do you have versus group data?

DR. KAY: With the cognitive testing, obviously we're able to test larger groups than we do in a driving situation. In fact, typically when we have a hundred subjects, a third receiving a positive control, the third receiving an agent under study, and a third receiving placebo. We're trying to find out whether there's any difference between the drug under study and placebo, and to demonstrate that we have sensitivity to sedation, we include a positive control, and with the size of the groups, we typically can look at specific groups.

For example, when studying diphenhydramine, this one we've been talking about, the cold, allergy and sleep medication, that we basically find that only a third report feeling sleepy. Actually, that was a recommendation by the FDA. Look and see what percentage of the people in your study are reporting sleepiness. We did.

Then we looked specifically at the two-thirds that didn't feel sleepy, and we found that those individuals were just as impaired on the cognitive measures as people who felt sleepy, you know, that lacked awareness.

So, yes, we could break it down. We have a large enough group. We can find out within a group what's going on.

DR. TEMPLE: But it's not just the little subset that's driving the mean; it's --

DR. KAY: No.

DR. TEMPLE: -- more than that?

DR. KAY: We analyze a study not just looking at mean but also non-parametrically in terms of the percentage of people showing an impairment. For example, on the psychomotor test I mentioned on Day 5 of dosing, 15 percent crashing would be abnormal versus zero percent on placebo.

DR. WEILER: Another issue would be to look at, as we do with the effectiveness responder, looking at an analysis of responders. We could be looking in this case at an analysis of those who have the adverse event.

The other thing that's really important to mention again is that the control groups that we use, if they're healthy people, are going to be different than if we use people who have allergic rhinitis, for example, in season, and it may be important to do the study in season rather than out of season.

So, we may justify giving them the drug out of season, and it may not be the same thing as coming in and driving when they're sick, they have a runny nose, itching and all the symptoms and feel drowsy to begin with.

So, a lot of variables, not just the dose levels, not just the reaching steady state, but the characteristics of those subjects in the study group would be very important when we're looking at impairment.

DR. O'HANLON: Our studies were typically done with 20 to 30 individuals, being patients or volunteers. That's too few, we agree.

As far as making an extrapolation of the population, we have two ways of doing that. First, at least in the healthy volunteers, we'd give twice the recommended dose. If nobody has responded or very few to the recommended dose, and they still don't respond to twice, we can be pretty sure of the safety of that particular drug.

Regarding are we looking at a few outliers that inflate the mean, in the case of seriously-impairing drugs, which antihistamines, by the way, are not in our view, then the drugs which cause more change in driving performance than the blood alcohol concentration .10 affect virtually everybody. That means 19 out of 20, 28 out of 30. If the effect is that strong, we are very confident that it is a consistent effect across our subject sample.

DR. KATZ: I had a question for Dr. Kay. You had said that your results on your -- if I heard you correctly, your results on your cog screen testing were predictive of real world situations.

I'm wondering which real world situations and which subsections of the -- or which specific tests or measurement functions were correlated with what those real world situations are, and that sort of raises the larger question, which is, what do we know on the basis of evidence about how these various test methodologies predict bad outcomes? Let's say traffic accidents.

For example, what's the -- Dr. O'Hanlon talked a little bit about the evidence for the lateral sway, but what about the various following closely as a parameter? That's, you know, the various sorts of things that people are looking at. What do we really know about how they correlate with what we really care about?

DR. KAY: Well, cog screen was a test that was developed for the Federal Aviation Administration as a measure to detect changes in brain functioning which left undetected could interfere with operational performance of an aircraft. It was based on a task analysis of the mental abilities required to fly an airplane, the cognitive, perceptual and psychomotor requirements.

It was later determined that it does predict performance of pilots. In a study done by a major carrier, it was shown that measuring operational performance of the person flying the plane, the commercial airplane, that cog screen was the better predictor than some simulator performance, whether or not the pilot had flown in the Air Force, his knowledge-based test, his IQ test, personality test.

So, it's a major selection tool.

It's also shown in studies where -- you couldn't do this in the U.S. but overseas, when we get the flight data recorder and measure landing performance, it was a good predictor of landing performance, and in studies where we have looked at pilots who've been referred for aviation performance problems, again looking at the overlap between those aviation performance problems, they have been rather striking.

The Navy has done studies in a different area, looking at landing performance -- rather, the landing craft that they used and found that cog screens, just using three or four subtests, was a very good predictor for them of who they could train to actually operate these landing craft, which is a fairly complex vehicle, and so those are some of the areas in which it's been studied, and we also looked at truck- driving simulation.

DR. SOLLER: Dr. Katz, just a comment in terms of when we use the term "predict real world" and then predict what's happening post-marketing, if that's real world, and a comment on that in terms of the drivers and machinery operators, the pilots.

There are compensatory strategies that might take place, avoidance strategies that might take place as well. Flyers are supposed to self-ground based on the condition, not necessarily the medication, but also if taking a medication, self-ground by way of example.

I had mentioned usage patterns before in terms of the particular dose and the variability, and with what we see as consumers reading the label and the type of labeling we have and what might be important in terms of added education, I think that provides at least a perspective in terms of thinking about how we think about predicting real world.

DR. KATZ: Could I just -- one quick follow up to Dr. Weiler.

What sorts of evidence is there linking the predictive power of the various submeasures that you look at and traffic accidents? Is there much

DR. WEILER: Well, I agree that what we really do need is real world experience from crash data and from the use of these drugs, and we are missing that link in many areas. We simply don't have a lot of good epidemiologic data.

Unfortunately, that wasn't what our panel was charged with, but I agree with the others who have said that that's the kind of information we need, that we can correlate with what we're getting.

The problem is that it's very hard to understand how someone who gets in a simulator or on-the-road driving has -- who is really impaired when you ask them to do tasks isn't going to have a problem when they actually drive a car. Do they have ways of compensating? Probably. But we really need data to look at this.

Many of the studies that have been done previously have problems. The crash studies really don't answer the questions very well, but I believe, and I've seen some more recent data that should be coming out soon that are helpful in this area and will provide us with this kind of information.

I think we need to encourage the collection of that kind of information to help us to correlate it because then we really are talking about the real world. We're talking about situations in which we collect data and look at impairment and not just laboratory experiments. I think we have to correlate the two and that will give us what we need.

I wasn't prepared to respond to some of that. I just hope those data come soon so that we can do that.

DR. ELLINGSTAD: We will be into that topic area this afternoon.

DR. TEMPLE: Anything, Dr. Kay, that you refer to, could you be sure that we know where to find it or that you provide the tests? Of course, Dr. Weiler, anything you can sneak us before publication.

DR. WEILER: Well, I'll see what I can do.

DR. TEMPLE: Actually, I had a question for Dr. Soller.

It seems likely that some people who are taking an antihistamine and are made sleepy stay home, but most people's lives aren't adaptable easily that way. If you have to drive to work, you drive to work, and I think seasonal allergies, you don't want to use your sick leave up for seasonal allergies.

Do you really think most people on those kinds of drugs, which are very widely used, really stay home and don't drive?

DR. SOLLER: I think consumers choose.

DR. TEMPLE: That's sort of what we're worried about.

DR. SOLLER: Yeah. No. But I think that's what you ought to also have confidence in, and the reason is that they have experience with these particular products. These products have been around for a long time.

There are alternates that are available, if these are unacceptable to consumers, and at least as we've looked at this particular situation, I won't repeat our position that we mentioned before, is that we're not necessarily seeing the signal, and that what is being done or what has been done by FDA and what will be done with the drug facts label will allow the consumer to make the best choice.

DR. GARBER: I think that probably concludes our questioning from the Technical Panel.

DR. ELLINGSTAD: Okay. We'll let the Tech Panel recharge their batteries, and we can come back to them when we're done with the parties.

What we'll do now is turn to the parties for questions. Again, our operating procedure here will be to ask one individual from each of the party tables to serve as the spokesperson. The rest of the folks, please give their questions and communicate them as intelligibly as you can to that spokesperson.

Let me also correct an oversight. At the beginning, I left off one -- the introduction of one of the party tables, our Professional Group, and what I'd ask you to do before you begin is, if you two gentlemen will introduce yourselves, and then we'll find out which of you is the spokesperson.

MR. GELULA: I'm Richard Gelula with the National Sleep Foundation.

MR. DROBNICH: I'm Darrel Drobnich, Senior Director of Government and Transportation Affairs.

DR. ELLINGSTAD: I think the mic's off there. Is the button --

PARTICIPANT: If you leave the button up, that will leave the mic on. It's up.

DR. ELLINGSTAD: Okay. Does this group have questions?

MR. GELULA: Yeah. I'm aware that different types of people are taking medications for different reasons. For instance, some people are taking medications to help them sleep. Others are taking them for cold, allergies, flu, or other medical reasons.

I'm wondering if the studies have compared the impairment effects for people, for instance, with chronic insomnia who would be taking the medications for the purpose of helping them sleep at night versus the impairing effects on the normal population.

DR. ELLINGSTAD: Go ahead, Dr. O'Hanlon.

DR. O'HANLON: Yes. We've always tried to do that with different patient populations, not only insomniacs, but with depressed patients and anxious patients as well, and to study them first in a controlled condition, not even with a placebo, to find out what their baseline performance is, and we have not been able with insomniacs or depressed or anxious patients to measure a baseline impairment. In other words, the impairment occurred after the administration of drugs.

One other thing. We have tried with our tests to produce an insomniac effect to limit people to only three hours of sleep before taking the test. We measured slight impairment but nothing like the impairments shown on -- at least in the worst cases to you this morning.

So, yes, it would seem that the morbid condition is not in itself responsible for driving impairment to any great extent as far as we've seen probably because the individuals have learned to compensate for their impairment.

A drug effect is something new, and I'd like to add to what's been said already. Often drug effects are to reduce a person's self-awareness, their insight and their judgment, and it's not fair to say to patients, you are the final person that decides whether you are fit to drive today or not. They're vulnerable, and drugs make them vulnerable to the mistake of driving in the first place.

DR. ELLINGSTAD: Any other questions from the Professional Group?

MR. GELULA: No.

DR. ELLINGSTAD: Okay. We'll turn to the Pharmaceutical Industry Group, and again as we go through, if the spokesperson will introduce themselves and then ask any questions.

MS. TAUBIN: I'm Lorna Taubin from the Consumer Healthcare Products Association, and I have a question for Dr. Weiler.

I was wondering if the methodology used in the National Advanced Driving Simulator, is that correct, is a unique facility?

DR. WEILER: So, the question is, is there a replication of what we do?

Actually, I should tell you that the facility isn't even on line yet. It will soon, and I'm not sure what soon is. In the next couple of weeks, hopefully. But there isn't anywhere else in the world to do exactly what's done in there.

The Daimler facility in Berlin has some similar attributes, but it's an older facility, and it doesn't have the track and so on. We can cross validate facilities like that with lower-end simulators, but there will be the need to do that, and it's something we're very interested in doing, correlating the end points that we'll look at with on-the-road driving and with lower infidelity simulators as well as some of the other cognitive tests. It's something we're very interested in doing. It's obviously important to do in a new facility of this sort.

I would also like to mention that there are additional materials available. I was made aware of this, that NHTSA has -- if you would like to have a much longer version of what I showed with more realistic video, we can make it available to any of you who would like to have it. It's not an advertising thing, but we can provide more background information if you would like to have some more.

If you'll let me know, I'll make sure that we get it to you.

DR. ELLINGSTAD: Any other questions?

MS. TAUBIN: No. I just wanted to add on that even when the studies are done there, that will be the only place that's using that methodology?

DR. WEILER: Well, in a sense, yes, but the idea is that we want to be able to use that facility to do other studies. We have a fixed base facility there, and the question is, when we look at this facility, when we set up our tests, what else can we do along with those tests to show that they correlate with each other? That will help us to understand situations in which we really don't need to use a facility like that, situations in which maybe we don't get the same data from two different kinds of tests.

We believe that it's extremely realistic, and we should have a great opportunity to be able to look at these kinds of questions in a scientific way.

MS. TAUBIN: Thank you.

DR. ELLINGSTAD: Thank you.

We'll turn to the Union Group.

CAPTAIN POPIEL: Randy Popiel, Allied Pilots.

My question has to do with tests and performance levels in the airline industry. Are there facilities, such as yours, Dr. Weiler, that are measuring aircraft operations and pilot performance with the use of drugs and sedatives?

DR. KAY: Well, there are studies that have been conducted, not too much with commercial aviators but we've conducted several tests with the Navy down in Pensacola, looking at specific agents. Two of those studies are now published.

One's currently in the current issue of Aerospace Medicine, looking at cholesterol medications, again looking to see if there's a sedative effect of these cholesterol-lowering medications, and this was done with several hundred pilots, using a test which is a predictor of aviation performance.

It was done using flight simulation, but there are studies that are conducted elsewhere that use flight simulation, looking at specific agents and comparing the active agent versus placebo to see if they affect pilot performance in aircraft, but I think there's more study going on now using cognitive and psychomotor tests which relate to flying.

DR. WEILER: There is indeed a literature using simulators, flying simulators. It should be said that it's easier to generate a flying simulator than a driving simulator because it's okay to feel like you're flying in a plane, but if you have a disconnect, you feel like you're flying in a car, that's the kind of thing that gets you sick and really invalidates what's going on because they may have simulator sickness, and it shouldn't really occur if you're driving a car.

So, it is difficult to build these things. They're not trivial developments.

DR. ELLINGSTAD: Any other questions?

(No response)

DR. ELLINGSTAD: Okay. We'll turn to the Transportation Industry Group, and who is our spokesperson there?

DR. FAULKNER: They say because I'm a doctor, I'm the one that should feel these things. I thought it was because I'm better looking on the megascreen up there, but we've been talking among ourselves here -- oh, God. Talking about some of the studies going on here.

As you're aware, in many of our industries, our employees are traveling for long times, over multiple time zones. Have there been any studies done not so much focused on maybe the medication but sleep- deprived individual employees and their impairment?

DR. O'HANLON: I mentioned one, and there have been others. I was not prepared for that particular question today.

Certainly sleep deprivation and particularly that which occurs in jet lag is responsible for impairment, but the psychomotor impairment which is manifest in driving impairment is not the biggest thing. The biggest thing is difficulty in sustaining attention, concentrating to a dull task like people's every day jobs, and to respond quickly and hurriedly like people would normally do.

There have been no tests that I know that show that people who fly over to Europe and get whatever poor sleep they can and try to drive around are in more danger or in greater hazard of an accident than normal, except, of course, they have to be familiar with their territory.

It is a problem but apparently not a huge problem inasfar as traffic safety is concerned. Work efficiency may be something else.

DR. ELLINGSTAD: I think we do need to restrict this -- our discussion here to the issue of illicit drugs. We can launch into a very large symposium, if we get into this whole issue of fatigue and sleep and so forth.

DR. GALSON: If the questioner would just identify himself for the record?

DR. FAULKNER: Tom Cruise? No. Dr. Tom Faulkner with APA.

Can I ask then a question, if we're talking about drugs? And I agree, employee fatigue is an extensive issue. Any studies you're aware of using the new class of anti-depressants, the SSRIs?

DR. O'HANLON: Which one? We've studied most of them, and my colleagues have as well.

The SSRIs have been extensively studied. Their propensity for producing driving impairment is very low. That does not mean it doesn't happen in an occasional individual, and it does not mean that impairment cannot occur when you're taking an SSRI and something else.

Doctor, as you know, there's the potential for a pharmacokinetic interaction with some SSRIs and other drugs, like example benzodiazepines, and my group has measured an effect, impairing effect of the SSRI or necessarily even the benzodiazepine but both in combination due to a pharmacokinetic interaction.

But in general, they're very safe drugs. I have more question about the mood stabilizers which are moving so heavily into psychiatry and even general medicine these days.

DR. FAULKNER: Final question. Seeing, I guess, interest in terms of the supplements, such as Ginseng, Ephedrine, St. John's Wort, Echinacea, any studies that you're aware of here or abroad on the impact of those used as a directed or in excess of directed?

DR. KAY: We have conducted several studies looking at NADH. We actually used it in a study on jet lag. I guess we could answer your jet lag question. We did find after flying people from the West Coast to the East Coast of the United States on commercial aircraft, this was done with, I think, all together 48 subjects in the study, that we found people were actually having trouble with undivided attention, about six-tenths of a second slower, which could have transportation impact.

We found if we gave them NADH, that we didn't find any deterioration in cognitive performance. They were talking about impairment. It seemed to have some protective effect, but we didn't see any side effects, comparing it obviously to placebo, looking at various ways to mitigate effects of jet lag, and we have studied supplements that way, and we basically use the same methodology with the supplements that we've used with the other prescription or over-the-counter medications.

DR. FAULKNER: Thank you.

DR. ELLINGSTAD: Any questions from the Transportation Industry?

(No response)

DR. ELLINGSTAD: Let's turn to the Advocates, and who is the spokesperson?

DR. de GIER: I'm Johann de Gier from ICADTS.

I would like to ask three questions to Dr. O'Hanlon. First of all, if you talk to physicians about the impairing effects of drugs, they mostly answer with the question that the ailment itself is also a problem for drivers and thereby the drug might have some improvement of the performance.

Did you, in your studies, ever look upon the placebo conditions with people with anxiety disorders, people with depression, people with sleeping disorders, to see how they behaved or performed under placebo conditions compared to healthy volunteers in the placebo conditions in order to see how this effect of the illness could be determined?

The second question is, how extensively have the effects of various sedating drugs prescribing in the long term prescribing of prescription drugs been studied with the so-called "at-risk populations"? For example, elderly, people diagnosed with several diseases but also people using multiple drugs or medicinal drugs, and then the issue you just mentioned, drug interactions is just one issue.

Should I raise the third question as well now?

DR. O'HANLON: Thank you. I'll try to remember.

I believe I mentioned that we did not see any particular impairment associated with depression or anxiety. I'll say that a little bit stronger. The anxious patients drove about as well as our healthy volunteers.

The depressed patients in our test paradigm drove actually a little better, and we measured them on two baseline days to see if they drove reliably better, and the correlation between their Baseline 1 and Baseline 2 was about .85, which is higher than we've ever seen in a healthy volunteer study.

It's difficult to get real depressed patients to drive a car in many cases, but when they could do that with all the assurance of our very nice driving instructors give them, they drove well in our test, and so they took drugs, in which case, some of them didn't drive well after that.

Now, as far as the at-risk population -- in other words, let me answer your question, as far as we know, patients unmedicated drive normally in our test paradigm, and there's only a little bit of epidemiological data to indicate that depressed patients in particular, when they're unmedicated, have a higher-than-normal risk of accidents.

Going to studies with populations at risk, we have studied elderly drivers, mildly cognitively-impaired drivers. They are worse. Unlike the younger patient groups, the elderly are worse drivers. The drugs that we were administering were not intended to make them still worse but make them better, and the drugs failed. So, all we know for sure is that the elderly are at more risk to any kind of insult, could be drugs or anything else.

Polypharmacy. Nobody studies polypharmacy as it's practiced. Now that I'm out in the clinical sphere, I see that every day, and I've seen much more drastic impairments as a result of combinations of drugs which extend in reality to 16 psycho-active drugs in a number of certain patients. I've usually just seen two or three or sometimes four.

We know nothing about that. We can suppose that this is an extremely dangerous situation for patients who still drive.

DR. WEILER: Can I make one comment? We've talked about a lot of variables that can occur when we do studies. We've talked about the underlying condition, talked about whether the person is drowsy to begin with, so they're sleep-deprived, and all of these other issues.

It's no wonder that it's a daunting task to answer the question, is this drug impairing? There are so many different variables that have to be considered to answer the question, and in some circumstances, they may be quite impairing, whereas in other circumstances, when the tests are run, we don't see a lot of impairment, and nonetheless, maybe it's the tests we're running to look at the effect.

So, it is a difficult task for us to answer these questions.

DR. de GIER: I would like to make a comment on that one, because I think it's always better to choose the least-impairing one, if you have a choice within a therapeutic class.

I would like ask the final question to Dr. Soller. Have you conducted any research or is there any data available to measure how patients make decisions about which OTC products to purchase?

DR. SOLLER: The types of studies that have been undertaken to look at individuals' label comprehension and then actual use were -- have their roots in a particular OTC class of drugs many years ago in terms of in-use effectiveness of a certain type of drug, and then in the early '90s, there was an interest, particularly in the RX/OTC switched products, and I think a good reasonably predictive set of types of studies, rather, developed, a label comprehension study and an actual use study, and these have been used and over the years have gotten increasing emphasis, particularly through the input from Dr. Ganley, who's here today, in terms of selection and de-selection.

The OTC new drug facts format has, during the development of the final rule for the drug facts format, there were studies that were undertaken by FDA supporting how that particular labeling is set up to ensure that you have a rationale flow of information from active ingredients to uses to warnings, absolute contraindications, do not use, relative contraindications, ask a physician before you use, in- use precautions, and then other information.

So, a lot of thought has gone into how to present that information to make it most successful and in a consumer-friendly way to the consumer.

DR. ELLINGSTAD: Thank you.

And the Government Group? Mr. Clarke?

MR. CLARKE: We have a couple of questions.

Dr. Kay, this question was asked somewhat similarly, but I'll ask it again, if I may.

Have any specific studies been done on older populations as relates to the effects of some of these medications, specifically focusing on the -- whether or not there would be greater differences in that population?

DR. KAY: Not in the studies that we've conducted with the cognitive psychomotor testing at the current time. We've not studied special populations, older populations like that.

MR. CLARKE: Anybody else with any other specific study results?

(No response)

MR. CLARKE: An observation by way of a question. It's been interesting to note over the past several years the increased tv ads for prescription drugs, and at the end of those ads, the extensive list of precautions and side effects and so forth.

Dr. Soller, by way of increasing the public's awareness of drugs and drug side effects, are you seeing any carry-over effects of increased public awareness of these kinds of concerns spilling over into the OTC arena?

DR. SOLLER: I'm not sure I know exactly what you mean by "concerns", but could you maybe just amplify for a moment?

MR. CLARKE: The advertising is obviously geared towards highlighting the beneficial effects of these various medications for different conditions, but then they also at the end talk about the potential side effects, which is the case with almost all medications.

Is it your sense that the public is reacting favorably to these ads in a way that would indicate increased sensitivity to concerns about side effects?

DR. SOLLER: I don't have any information specifically on that. Dr. Spilker might. I think in looking at direct consumer advertising of prescription products versus OTCs, it's important to recognize that advertising is best used in terms of raising awareness about what a product's for and where they might be able to get it.

In the terms of the learned intermediate that might be there for the prescription product, and a consumer having information to engage in the dialogue with the physician on that particular point and what DTC might use be done in that area.

I think there have been some reports on that. I can't speak specifically to them, but from an OTC standpoint, it's important to think about the use pattern where the individual picks up the product, has it in their hand, and how do you present the best information for them so that they can read it, as I mentioned earlier, in that logical flow of information, so they can get all of it in a consumer-friendly manner with bulleted points that give it chunks of information that they can take away with them?

So, I think, as I've mentioned before, I think what we are about to do in terms of the implementation dates for drug facts labeling, that we're in a position to raise the level of awareness on some of these warnings because they will be more prominent and more consistently placed on the label.

DR. SPILKER: We know that the public and patients in general are very pleased with the direct-to-consumer advertisements, based on a large number of surveys done by a wide variety of consumer and other groups.

The patients are looking for information. They are going to their physicians in many cases, and once there, one of these, if you will, side effects of this type of advertising is diagnosing heretofore undiagnosed problems.

There are large numbers of patients with diabetes, hypertension, and other chronic diseases who have had this disease diagnosed and treatment initiated based on their going to physicians for direct -- as a result of direct-to-consumer ads.

Vis a vis your specific question on the adverse reactions, I think that that information that is presented both through the ad, both through handouts at the pharmacy and through discussions with their physicians and other health care professionals, is all to the good because it is giving this -- informing the patients and encouraging them to take more responsibility for their own care.

I think that the -- rather, we know that the objections of the physicians to the directed consumer ads have been decreasing over the last half dozen years, and the objections of the AMA also have decreased. While there still are some, the physicians are recognizing the benefits of the information which does include the adverse reactions.

DR. O'HANLON: I would like to say something about that.

Since old Merrill Dow began the directed consumer advertisements with Terfenadine, extolling the drug's lack of behavioral toxicity, I have heard very, very little in television advertisements concerning effects of drugs that can impair skilled performance and even dangerously so in the case of driving.

I wonder why you asked the question, because it seems that if the manufacturer has any suspicion that there may be a behaviorally-toxic effect of the drug, either directly or in interaction with another, we do not hear about that on television.

MR. CLARKE: The question was a general one, whether or not the advertising is increasing awareness on the part of users/consumers that there are side effects that they need to be concerned about. I wasn't focusing on any one particular type of side effect but rather just the whole issue of side effects as a secondary effect of taking this thing for positive reasons.

One other question. I think it was Dr. Soller made his comment about this 18 primary and five secondary AERs in 10 years with 850 million prescriptions. Can you elaborate a little bit on that study or -- I found that fascinating.

DR. SOLLER: Let me turn to a chart that I should have here, if I could. Lorna, do you have the

-- no. The attachments?

We had undertaken a review of the adverse experience reporting profile for the antihistamines that were listed in the slides that I showed. These were OTC monograph antihistamines. Some are covered under an MDA for OTC use, and they're used for cough/ cold purposes, allergy, antiemetic use as well as sleep aids, and they have both OTC and prescription use.

We went to IRI to get an estimate for -- I can't see you. There you are. IRI to get an estimate of what the unit sales would be over this particular period of time, and it was estimated in the subpopulation that we looked at, the individuals who were 16 years and older -- we were figuring drivers licenses. We took that age break, that approximately 850 million packages or what we call units were sold over this period of time.

Reflecting the overall usage, I would expect that that is probably higher because there's prescription use, too, that we did not go to IMS to get the script information.

Then as we looked at this, the total serious AERs as they were defined in the MedWatch System, that would include hospitalizations and so on, were 23 in number. There were 18 serious AERs for individuals over 16 in accident terms for the antihistamine listed or reported to be listed as the primary suspect. There were five where they were listed as a secondary suspect, and in about seven of those 18, there are probably other reasons.

For example, there were two subarachnoid hemorraghes. There was a cerebral infarction. These are rare events, and there were falls. So, the point of this, though, I mean, you can get into all the details, and I'm not going to go any further, is that over that 10-year period, there was nothing more than about four per year that were being reported.

MR. CLARKE: That was my question. These are events that are reported back to the manufacturers, is that it?

DR. SOLLER: These would have been reported to manufacturers and to FDA by health professionals, by consumers, by people that may be monitoring drug studies.

MR. CLARKE: Thank you. That's all.

DR. ELLINGSTAD: Okay. Thank you.

I'll ask the parties to consider one final question, if you have one, but before we do that, Dr. Galson has got some questions that have been submitted by the audience, and I'll ask him to pose those to the panel.

DR. GALSON: Thanks. We have received four questions. One is a multipart question, and one of them is not really pertinent. It has to do with effects of a specific medication, which is a medication for pain, and we're not going to talk about it because we're not talking about pain medications. We're also not talking about specific drugs.

So, I'm going to put that one aside but just to acknowledge the question, and I'll have to talk to you more about that at the break.

The first question I want to raise is to the whole panel. Can you please comment on the use of PC-based virtual reality driving simulators to evaluate impairment?

DR. WEILER: I'll try to address that one. There are some problems with them. The problems that are faced sometimes with the lower-end simulators has been sickness, simulator sickness, and that's been an issue that's been raised.

So, many of -- there are a wide range of simulators that are available. We had a symposium last week, a meeting last week in Iowa City of people who do simulation research, and I was struck by how many different kinds of simulators there are. There are a lot of options for people to do these kinds of studies, ranging from NADS to low-end simulators that are PC-based or that use some kind of virtual reality, and each one of them has their own special advantages.

Maybe on the low end, the advantage would be low cost. On the high end, it would be the reality of the actual driving experience. So, there are data on using those. I'm really not prepared to address for each product how it would be, but again, it's the level of complexity that we're talking about here, and how we define what is an impairing drug.

DR. O'HANLON: We all are to respond to this, is that correct?

DR. GALSON: Anyone who wants.

DR. O'HANLON: Okay. I know of no investigator that engages in full-time research on drugs and behavior who uses them. The reason why is because an instrument is not a test. Tests have to be developed and embedded in instruments, and it's usually easier to do, as my colleague Dr. Kay has done, to use something that's easier to control. It's not as much fun as a video game, but it is a lot more scientific and reliable.

The question with all simple devices, including PC-based simulators, are, are the results they provide valid in predictive purposes for showing a drug's behavioral toxicity? That has to be shown for the test, not the device.

DR. KAY: We are currently engaged in research actually with the Centers for Disease Control. We're doing some current work looking at the relationship between low-cost PC, you know, desktop PC-based driving simulation and how it relates to actual driving, to do that development of it as a test, but we have conducted studies with pharmaceuticals using the virtual reality-type driving simulation to look at dizziness brought on by Floxins, certain antibiotics that people might take, and we had a downtown driving task, and what happens is people who were dizzy don't turn their heads as they would need to do to see pedestrians in the crosswalk and were running over pedestrians.

So, it's quite an interesting demonstration of what was occurring with a CNS side effect, but, you know, we are -- there is a problem still in terms of development with the simulator sickness, but that's being responded to by improved kind of graphics which are very important.

DR. SPILKER: Your question, Dr. Galson, and all of the discussion this morning really brings out the point that there is no gold standard and no universal standard for measuring impairment which really is the subject of this session.

DR. SOLLER: Just a brief comment, and with considerable respect to Dr. Weiler for being involved in creating what is a very complex design, must be fun to operate that design, and I was very much taken by your comments, Dr. Weiler, at least as I interpreted them, that -- and I may be overstating this.

I apologize, but simulators do simulate and that doesn't take away from the design that's created within that simulator setting, but it does speak to what might be the missing link, and the need for, as I heard Dr. Weiler speaking, and I would agree, correlating the information from the simulator to the real world, looking for correlations across simulators.

DR. GALSON: Okay. Great. The next question, again addressed to any and all of the panel members, is, is there a relationship between an individual's baseline level of cognitive function and the likelihood of becoming impaired by a drug?

DR. KAY: If I can answer first, in our studies actually in order to conduct good cognitive trials, good clinical trials, we generally will screen out individuals who are at the lower ends of cognitive function.

If they can't actually take the test and provide reliable data, then we actually don't include them in our trials. So, there would be a screen-out, an exclusionary criteria for inclusion in the study. Whether having high IQ or high cognitive performance might be a protectant effect, we've never really looked at or analyzed our data in that regard.

DR. O'HANLON: I was very fortunate when I retired from the drugs and driving business about three years ago to find myself in an even more challenging occupation, and that is, working with the developmentally disabled who use drugs, and I can only tell you, whoever asked the question, of my personal observation, that the drugs do have quite different effects sometimes in people with borderline intelligence and mild mental retardation.

How this relates to the topic of this conference, I'm not sure, but it is possible that the drug effects could be different in drivers at the low end of the, call it for lack of a better word, intelligence spectrum possibly but not shown.

DR. WEILER: And that may not be the only issue that we have to consider. We may have folks with ADHD who may have an impact on their driving performance that's unrelated to their underlying condition of allergic rhinitis or whatever. That adds another level to the complexity in trying to sort out the effects we might see with these drugs in those people.

DR. GALSON: Any other responses to that question?

(No response)

DR. GALSON: Okay. The last one is the multipart one, and it's addressed to Dr. O'Hanlon, Dr. Spilker and the remainder of the panel. So, maybe the two of you could speak first, if you have comments on this.

Do we have sufficient data to suggest a known period of impairment for sedating drugs?

DR. O'HANLON: For some, yes. I would like to make a general remark. We know enough now to be sure that prescribed medicinal drugs and presumably some OTC drugs kill people, and driving situations are the primary cause of their driving accidents.

If we wait until there's complete consensus among all the investigators who study these effects and a standard universal methodology, we wait forever. Now, to go specifically to the question, yes, because of epidemiological research and also some empirical research, we know that the period of danger after certain drugs, specifically benzodiazepine tranquilizers and hypnotics, which were once very popular and gave us a good database, is maximum during the first week, but it is not gone for a month.

In driving, the risk, as I mentioned earlier, the risk of an injurious traffic accident, when you are taking a benzodiazepine tranquilizer during the first week is about 13 times normal. By the end of a month, it's about only two times normal, and there's a nice exponential progression of relative risk from the 13 in the first week to two at the end.

We see similar changes in empirically-measured driving impairment. It's maximum right after the drug begins. It is not gone at the end of the month. Okay. But whether and how this applies to all other drugs, we do not know. Some drugs, we suspect, get worse over time due to accumulation or late-emerging side effects. We have not shown that empirically yet.

The second part of the question was?

DR. GALSON: I didn't read it, but why don't I go ahead and read the three parts of the question, since they're all very closely related.

DR. O'HANLON: My colleagues would also like to respond.

DR. GALSON: Let me read all three because they're related. I think it will flow a little better.

The second one is, would it not be prudent to specify a time range that driving performance might be impaired? The third part is, why not err on the side of conservative and specific advice, that this drug may cause drowsiness on a label seems to be non-specific and weak to guide most people?

DR. SPILKER: I'll start with the first part of the first question. If a drug is believed or is known to cause impairment, then obviously this should be studied in terms of the time at which the impairment is going to occur, both the onset, duration, range for different groups, if it's found to be different, for example, for men than women, possibly for different ages, different fat content, depending upon the distribution of the drug in the body.

Basically, we're saying that you've got to study this, and I'm confident the FDA would demand this of the companies that are investigating this drug. The information on the range certainly should be put in the label which really, I think, gets to the second part.

Certainly it's prudent to give this information out because just saying a drug causes drowsiness or may cause impairment is not giving as much information as for other adverse reactions or just given as a statement.

Now, I do believe that when a drug is known to cause impairment, that this is studied by the companies. I obviously can't talk about all drugs and all situations, but I do believe it is very relevant for companies and FDA to agree on a mutually-agreed-on process by which they will evaluate this consideration.

DR. SOLLER: I'll just make a comment, if I could, reacting to the comment that we shouldn't wait forever, and I'm not saying that everything has been done for all drugs.

But I don't think we've waited forever on OTC medications. By way of example, we tracked the experience of our products. OTC labeling has been very carefully devised over a very extensive public rulemaking process. There are quite a number of different on-going educational efforts, and we participate in them. We think we can do more here.

We look for ways to partner with other organizations to amplify the message, and on the issue of the specific label language, I think it's important to tell people what they most likely can look out for and that was debated within the development of the final monograph for antihistamines, for example, and there is a very specific statement, a precautionary statement about driving motor vehicles and about operating machinery.

I think in the end, in looking at this, in looking at what is done and what will be done with drug facts label and understanding what we have by way of experience, I think we're on the right track, at least for this class of drugs. I'm not speaking for others that have been brought up today.

DR. KAY: First off, I'll comment on the duration, and I think it is important that methods be used that look at the duration of effect when sedation is likely to occur and for what period of time, and I'm not sure if that methodology is there and if those standards are there because the methodology certainly isn't.

With Palm Pilot, for example, we could find out when people begin to report feeling sleepy. A study done recently with Cisterazine, which is an antihistamine, showing the sedation was delayed. It's not like what we see with the over-the-counter antihistamine. It was like about four hours later. The same thing on the SLT, the sleep latency test, looking at the sleepiness isn't there an hour and a half. The first nap of the day isn't until like, you know, 1:00 in the afternoon, 3:00, four to seven hours after we dose.

So, it's important to know when sedation -- when's the onset of sedation going to occur, and how long is it going to occur for, and I don't think the bottom line is, you know, how much driving is going to be affected as how much impairment is going to occur.

In our studies, we've looked at Chlorpheniramine, an over-the-counter antihistamine, looking at duration of effect. We've seen impairment of about 15 percent of performance at seven hours after dosing, and so, you know, you see an effect of this duration. We're not saying how much that impairs driving, but if you're working, it's an impairment of your ability to do your job. If you're a student, am I going to be impaired, my ability to learn when I take this medication?

Just saying may cause drowsiness, I think the answer for some drugs is this drug will probably not make you feel drowsy. It will just impair you, and I think we need to let people know when that's likely to occur.

DR. SOLLER: Two comments, if I could. Just by way of information, I don't know. The study on Chlorpheniramine, was that the OTC dose of four milligrams or at the eight and 12 that you described?

DR. KAY: That was actually a study that was done with two and four milligrams.

DR. SOLLER: The other thing that I came across and had not thought we would be getting into this, but there is at least one study I'm aware of that looked at antihistamines and the performance of children in school and did not find an effect. So, there is some information. I didn't find a lot of information.

DR. GALSON: We'll have the opportunity to discuss some of these issues more later in the meeting. So, don't feel like we have to discuss it around the table right now.

DR. WEILER: But this does bring up the issue of having a profile for each medication that helps us to understand the onset of adverse events, such as impairment, if it's going to occur, and how long it lasts. Really, it's important that we have the profile for each drug. If we really believe it's impairing, we need to know the degree of impairment with each agent, and it's not a class-specific thing certainly.

There are really differences amongst these drugs, some which are really mildly impairing and others which may cause a significant amount of impairment and may last for a long period of time, just like the class we consider non-drowsy, may have differences amongst them, if there's dose-ranging differences and so on. Again, it makes it difficult to answer the questions. It's not a simple yes or no answer often.

DR. ELLINGSTAD: I think we'll try to get ourselves somewhere close to schedule, but I promised another quick round, and I'd ask the groups, the parties, to keep the questions focused specifically at individuals on the Witness Panel and keep them reasonably concise.

First, with the Professional Group.

MR. GELULA: Thank you.

I'm thinking about a particular class of people, those who are needing to sleep but perhaps battling a circadian situation, like a pilot who has flown overseas, has a lay-over time, has to sleep in that time, a truck driver whose time is regulated and must sleep in a fixed period of time, regardless of what time of day or night that is, a shift worker, etc., and I'm wondering, going back to Dr. Weiler's suggestion that there is a need to differentially rate the impairment of sedating medications, and Dr. O'Hanlon summarized the data showing a great deal of impairment variability among long-acting versus short-acting hypnotic medications.

Given those two things, and this probably relates back to some of the points that were just made, should not those particular cases where the impairment effects are known be brought to the attention of those work groups?

DR. WEILER: Yes.

DR. O'HANLON: Yes.

MR. GELULA: Second question.

DR. KAY: I would say we've tried even showing that information with the aviation industry in terms of night-time use of over-the-counter medications which they may assume isn't going to have an effect on them the next day when they have to get up and fly the airplane. So, we've been trying to get that word out.

DR. WEILER: Again, we don't want to trivialize the warnings. There are so many warnings on so many things, that you pick up everything, and it has a warning on it. So, at a certain point, you say I guess I'm not going to worry anymore and that's not what we want to do here.

We want to tell people these warnings are serious, and we want them to be concerned about these issues, and we may not be able to run every last test to determine in every last circumstance the degree of impairment. We have to make some assumptions, and I guess what we're saying is the assumptions we make are the taking of the worst case or a reasonable case that would suggest to people it's probably not a good thing to take a drug such as diphenhydramine if you're drowsy to begin with and making a long trip.

MR. GELULA: But if I read you correctly, it might be appropriate to take a short-acting hypnotic in the situation where it's better than not sleeping at all.

DR. WEILER: It might.

DR. O'HANLON: Oh, I think it would in fact. There are drugs that I have recommended for that purpose precisely, but I'd like to go to my colleague's remark about it not being a good idea to take 50 milligrams of diphenhydramine or even 25 four times a day just before you're going to drive from here to Sarasota.

There are alternatives. They might cost you a little bit more, but there are alternatives that myself and my colleagues have shown to be much safer.

MR. GELULA: Let me ask you another question. How effective is caffeine as an antidote to the sedating effects since that's what people will often do?

DR. O'HANLON: Well, it's not a good antidote to alcohol's effects, has virtually no physiological antagonistic activity against a reasonable blood alcohol concentration.

I can't tell you how it would be for every single drug, but because the pharmacology of caffeine is different than the pharmacologies, plural, that cause sedation, they're not direct pharmacological antagonists. It would be a guess on my part. I'd rather not speculate. I wouldn't count on it myself.

DR. ELLINGSTAD: I think we're getting a little bit beyond the scope of this panel. If we can move to the Pharmaceutical Industry?

MS. TAUBIN: I don't have any questions at this time.

DR. ELLINGSTAD: Okay. The Union?

CAPTAIN POPIEL: No questions.

DR. ELLINGSTAD: And the Transportation Industry?

DR. FAULKNER: No questions.

DR. ELLINGSTAD: Advocacy?

DR. de GIER: First question is actually, are any of the driving tests, whether real world or simulated, involve multitasking by the driver who has taken drugs or are the drivers charged only with controlling their vehicles?

DR. WEILER: Well, I can answer in the case of simulator studies that we've run. There are many end points. In fact, there can literally be hundreds. In the one study that I talked about, I think there were 70 end points in the protocol we looked at, and in fact, that's an important issue because when we look at drugs, such as alcohol, which is a divided attention task-impairing activity, when we looked at the primary end point, we saw that they did okay, and if we just let it go at that, you could say oh, it's okay to drink and drive and that's not a good conclusion by anybody's standards and that's a good point.

We really need to look at the multitude of end points that you look at in order to define the kind of impairment that you see. So, it is important we look at that and that's why comparing not only a driving task itself but also some of the other activities we can look at, such as subjective report of drowsiness and the subjective report of how impaired you feel, plus other cognitive tests, may help us to define really well the profile for each product.

DR. O'HANLON: As far as the actual driving tests are concerned, I described only the standard tests that we have used so long because methodologically, it's a lovely test. It's very limited, however. It measures only direct vehicular control in two dimensions.

My groups in the Netherlands have gone on, it began while I was there but have gone on to develop a car-following test and also tests for urban driving which involve the measurement of eye movements to catch cross traffic at intersections. These are not standardized to the same degree, and they have not been -- they're evolving still, and they're changing from study to study.

The point I would like to make is that these more complex, you call them multitasking tests, they could possibly and probably be run in a simulator, not necessarily the one I was conversant with, and at the same time that the tests go on in the real world, and if they do agree regarding the hazard potential of certain drugs, I think that this complement is perfect.

I mean, it must understand that this is not an either or situation when it regards methodology, use the best methodology for the purpose, but you might have to combine the methodologies.

DR. WEILER: And I would agree with that. We looked at some technologies last week at our meeting, and there were actually some vendors there that had some equipment, and much of this has been implemented in real cars and real drives, and we believe that's absolutely essential, that we have to look at real driving.

We don't look at just one particular scenario, one particular environment, but real cars, real simulators, added together to give us information upon how these could be useful in detecting impairment, and I mentioned some on the slides, such as glance, head movement and so on. These are very important tests, and we're going to be studying these obviously.

DR. ELLINGSTAD: We're going to have to go to your final question.

DR. de GIER: Yes, it's a very quick one, just for clarification, because it's for Dr. Weiler. Has impairment or other negative reaction important for driving been documented after using anabolic steroids? Is that what you just gave in one of your lists?

DR. WEILER: I gave that as an example of the drug that could be studied. I believe there's one paper somewhere. I don't have it with me to give you the reference.

DR. de GIER: Okay. We would like to see that. Thank you.

DR. WEILER: There's been some work in the area. I don't have the references with me. I know that we did a search on the list of drugs, and it certainly popped up as one that had a number of hits.

DR. ELLINGSTAD: Thank you.

And the Government Group?

MR. CLARKE: We don't have any questions, Mr. Chairman. Thank you.

DR. ELLINGSTAD: Okay. We do have one presentation, but before we get to that, I'd like to ask a very brief question of each of the members of the panel.

On the basis of the research that you're familiar with with respect to impairment, is it feasible to develop a list of medications or classes of medications that may safely be used when operating a vehicle? Dr. Weiler?

DR. WEILER: Yes, I think we can certainly develop lists of drugs that appear to be relatively safe and those that appear to be relatively impairing on the extremes. We'll argue about some that are in the middle perhaps, but I believe that we could come up with some lists that we could be relatively comfortable with under general circumstances, given all of the many variables that could be considered when we generate such a list.

DR. ELLINGSTAD: Dr. O'Hanlon?

DR. O'HANLON: Dr. de Gier's already prepared such a list with his colleagues, and it's widely accepted. It needs to be updated on, but what you're asking has been done several years ago.

DR. ELLINGSTAD: Dr. Kay?

DR. KAY: I believe the answer would be yes to that.

DR. ELLINGSTAD: Dr. Spilker?

DR. SPILKER: Whether the answer is yes or no, I would question the wisdom of developing that list and putting that out because I do believe that there are patients, whether it's those cognitively-impaired, whether it's those with certain psychological issues or those who just react differently to drugs, given the large individual variation, and even if in the clinical trial, you find a number of cases of drowsiness or sedation to be the same in a control group and the drug group, when you're in open label or you're just taking a drug, it's still a hundred percent for you. So, I really would question the purpose of it.

DR. ELLINGSTAD: The question was, on the basis of the literature that you're aware of and the research that we've done, is it feasible to do it?

DR. SPILKER: I'd say it creates many problems to do that.

DR. ELLINGSTAD: Okay. Dr. Soller?

DR. SOLLER: Yes, I reflect the similar view. I think there's a caution in looking at that kind of list because of the potential of overstating what the particular effect might be, and the questions we've heard today in terms of which particular parameter you're going to look at.

From an OTC standpoint, I've said it, I think, more than once this morning, that the focus has been on what the warning label would look like for the consumer, and so in that regard, focusing, I believe, from a consumer standpoint, and I know there's a larger public health perspective with patients here, but from a consumer standpoint, focusing people on reading the label, the new drug facts label will get them into the warnings and give them the information they need.

DR. ELLINGSTAD: Thank you, and I'd like to thank the panel very much. This has been a very useful information-gathering activity.

We have one presentation from Ms. Karen Tarney of the Citizens Against Drug Impaired Drivers. If you would come up to the podium here, and again I'd remind you that we're confining these to a five-minute presentation, and we will not have an opportunity for questions.

Open to Audience Discussion

MS. TARNEY: Thank you, and I would like to make just a general -- couple of general remarks.

My organization, Citizens Against Drug Impaired Drivers, also known as CADID, has been working in this area for 12 years, and part of our mission is to reduce the number of crashes and fatalities due to prescription and over-the-counter drug driving impairments.

I'd just like to share a few observations with you of what we have found. There's very often a not-me syndrome because people who look at taking medications, whether be they over-the-counter or prescription, are generally the average citizen we're talking about, not the person who goes out to abuse drugs, not the person who drinks, but the average every day citizen who says I'm a good person. I don't take drugs. I'm just, for instance in prescription drugs, my physician's orders, and if my physician has prescribed it, it's okay.

As far as over-the-counter drugs are concerned, if it's over-the-counter, people often believe it's harmless. If you add to that mix cold, flu, winter driving, certainly where I come from, or spring with rain, snow, sleet and the allergy medications, we have prescriptions for crashes, and if we take the two highest crash rate groups of the elderly who mix many of these medications or the teens, the young people, we then have a major, major problem.

I propose that people do often ignore the labels on the over-the-counter drugs. They ignore labels on the prescription medications. Not everybody is able to read. People vary in the combination of drugs that they take, and different things during different times they're taking the medications will impact whether or not they become impaired.

Physicians do not necessarily know all the drugs an individual takes, and they don't necessarily want to always get involved in the arena of counseling people on the drug and driving issue because they don't necessarily know what the law in their state is.

I would like to see a very simple label that is very dramatic that comes out of the FDA that will have universal meaning to everybody, even those who can't read or who don't read.

I would also like to tell you that there are ways of arresting and tracking and looking at the impairment from the legal side, and I don't think we will ever solve this problem until we join hands with law enforcement, and within the law enforcement community, there is a group known as Drug Recognition Experts.

These people have been specifically trained to detect drug impaired drivers. Thirty-four states and five countries have approximately 4 to 6,000 drug recognition experts that are trained. This is not well publicized, and I think that this is -- that we need to take our -- join hands with these people because they've done years and years and years of research on simulators, not simulators, the driving tests, as to what are the drugs that impair the driving? What are the laws, and what will get people's attention?

I also think unless there's a deterrent for the public, as much warning and education as we do do, I think that it will be mildly effective, and I think it's very heavily needed. I don't think -- I think what really is the big deterrent is whether they will be arrested, especially among the young people where they've just gotten their licenses.

I propose that there are uniform standards in pharmaceutical products that every state needs to follow, and a uniform reporting system for prescriptions so that people don't go from pharmacy to pharmacy to fill the prescriptions.

I'd like to also see alternative dosing schedules. I'd like to see the physicians become educated in the role of counseling people with the driving because they may be prescribing two or three drugs and then the person goes to the next doc and the next doc and the next doc.

I think a lot of the work has already been done through the drug recognition -- the Drug Evaluation Classification Program which is the name of the program that is run by NHTSA and the IACP, International Association of Chiefs of Police, and the people that are trained are called the drug recognition experts.

We have worked and talked with the public for 12 years in predominantly what I see as a bunch of blank faces, and the biggest group that is very, very worried about this is the elderly, but the elderly are not necessarily always able to handle their own problems.

I propose that by the end of today and tomorrow, that we come out with looking at a holistic approach and a much better solution in working together. I think a lot of the information is already out there, and I think -- I'm just thrilled to be here with this symposium because we have done this for 12 years, and I'm glad to see other people beginning to recognize it.

Thank you.

DR. ELLINGSTAD: Thank you, Ms. Tarney.

We are very close to schedule. I realize we've got an anxious Technical Panel that hasn't had all of their questions answered, but we hope to give them the opportunity to gather this information in other ways throughout the rest of the day and also tomorrow.

We will resume at 12:50 promptly, and we have three panels this afternoon. So, we're going to have to try to keep ourselves as close to the schedule as we can.

Thank you.

(Whereupon, at 11:47 a.m., the meeting was recessed, to reconvene this same day, Wednesday, November 14th, 2001, at 12:50 p.m.)

A F T E R N O O N S E S S I O N

12:50 p.m.

DR. GALSON: Folks, could you take your seats, please?

I'd like to kick off our afternoon session today with the second Witness Panel, and the focus of this one is Epidemiology. We've got four witnesses here, and we'll start from the right side.

Again, a few reminders. People in the audience who may want to ask questions should write them down on cards and take the cards up to the women standing in the back from FDA, and they will bring the cards up to us.

The speakers should try to limit themselves to five minutes, and again the parties should appoint one of you to be the spokesperson. It can be the same person or it can be a different person from last time.

So, I think with that, we'll go ahead with the first speaker, who is Dr. Fiona Couper, and she is with the Washington State Toxicology Laboratory, the Washington State Patrol, in Seattle.

Thank you.

Witness Panel II - Epidemiology

DR. COUPER: Thank you.

Good afternoon. Well, in this brief presentation, I'd like to answer the following question: how do we know that a person's use of prescription or over-the-counter medications (a) may affect their ability to safely operate a motor vehicle and (b) contribute to accidents?

And as a forensic toxicologist, we're often asked to answer this specific question in court after driving under the influence cases.

To answer this question, we rely basically on four different data sources or information, and I'd like to break these down into two different groups. The first group is the perspective information and that's the pharmacological information, usually from the drug manufacturers, laboratory studies and driving studies, which in this morning's presentation, they covered them a lot, but also we rely on this fourth group of data sources, the epidemiological studies, and this is more retrospective, and I'll go briefly through all of these.

Basically for the pharmacological information, primarily we look at the nine pharmacological effects of the drug, the primary therapeutic indications. If it's a sleep inducer, we know that it's a sedative or hypnotic drug, so the primary effect will be to sedate the patient. The known desired effects and also the adverse reactions.

The pharmacology. We like to get information on the peak time of effects. So the peak effects, is it an hour after taking the dose, is it two hours or is it four and five hours after the dose? The time of the day the drugs are meant to be prescribed. If it's a night-time medication, are the patients actually taking it before they go to sleep or are they taking it in the morning?

Other things. Interesting to know whether the drugs have active metabolites because after the parent drug passes through the body, sometimes the active metabolite, as I said, is still active and that produces a therapeutic or an effect in itself.

Also the age of the individual. We've mentioned elderly people often are more affected by some of these drugs. Gender, and a lot of the patients will develop tolerance to some of the pharmacological effects over time.

Also very important area is the known drug interactions, whether it's alcohol or other central nervous system-acting drugs, and finally, drug manufacturer recommendations. You often find these in the PDR.

Laboratory studies. This is -- I'll just briefly go over these. It's been mentioned this morning. These demonstrate whether a drug produces a dose-related impairment of cognitive and/or psychomotor functions in a laboratory setting, and these often don't simultaneously test for all the psychomotor performance functions that are required for the safe operation of the motor vehicle, but they're great studies to look at.

The actual driving studies, as mentioned before, like the driving simulator or the actual on-the-road driving tests, these attempt to duplicate real life situations. So, they go a step beyond the laboratory studies.

Quite often in toxicology, it's the epidemiological studies that we concentrate more on. Firstly, a lot of these studies will actually give the incidents or the extent of drug use in a population, whether they be actual driving fatalities or just driving under the influence cases. So, epidemiology is after the fact, after someone has been pulled over for a driving under the influence, after they have died, after they've been involved in an accident and taken to the hospital.

We also look at actual case reports, and this is a great source of information, particularly for toxicologists, and it shows great evidence of driving impairments, and as mentioned before, the DRE, the drug recognition evaluation officers, toxicologists work closely with them.

The police actually or witnesses observe the erratic driving, observe the car weaving all over the road or causing the accident. Often the DRE officers will then perform field sobriety tests, so the driver will be asked to walk a straight line, touch their nose and so on, and so they can get an indicator of how impaired the driver is, and this is backed up by the toxicological tests, where the toxicologist tests the blood and urine specimens and confirms that the drug was present.

We also have responsibility analysis or culpability studies. Wayne Jeffery will be talking a bit about this later. There was also a great study by Olive Drummer in Australia that provide a risk assessment of the role of the drug, and often they can account for -- they usually have controlled studies as well, so they can account for the accident was caused by weather conditions, road conditions, car conditions, medical conditions, fatigue or other drugs when present. So, if a drug is involved, they can reasonably conclude that that drug may have caused the impairment or may have caused the actual accident.

Just to give some examples now, I've just given a brief overview of what information we use. So, I'll give two examples. Firstly, the benzodiazepines as a class of drug. So, we look at the drug information. They are used as sedative hypnotics, anti-anxiety and muscle relaxants. So, this is the primary effect that it has on the body.

You have both short and long duration of action with the benzodiazepines. Their primary effects last for about six to eight hours, and some will last longer, 12 hours or 24 hours later. They may cause drowsiness, dizziness, confusion, lethargy. This is all in the PDR, and some of them, like diazepam and lorazepam, they often cause residual hangover effects. So, if you take them before bedtime, you actually have some effects the morning after, and as I said before, some patients can become tolerant of some of the effects of the benzodiazepines.

Just down below, this is what it actually says in the PDR for the drug Alprazolam, which is Xanax. The PDR, the manufacturer suggests patients not operate dangerous machinery until they appreciate the effects of the medications and warns the drug effects may be additive to those of alcohol or other CNS depressants.

If you then go to laboratory studies, most of the laboratory studies across all of the benzodiazepines state that single therapy doses are capable of impairing cognitive and motor performance, again tolerance may develop, but again the effects of alcohol and the CNS depressants are additive.

Driving studies. Significant impairment of example tests that test for lateral position control, visual perception, speed control and anticipation of hazards.

Then going to epidemiology studies, again this is like the incidence of. You take fatalities or DUI cases. How many of these cases, what percentage have benzodiazepines present, and we've found that benzodiazepines are the most frequently-detected illicit drugs. So, prescription drug or over-the-counter medication found in accidents and fatalities.

Although the percentage is quite low, it is, as I said, the most frequently-detected drug.

And from case reports from police studies and toxicology studies, the police have found that these drivers are often uncoordinated, disorientated, drunk-like, so they're stumbling. They just appear like they're drunk.

The responsibility analysis. There's been some inconsistent results with the responsibility analysis. This is mainly due to the wide range of benzodiazepines studied. Different doses have been studied in different studies. Some of them are short-acting, as I said. Some of them are long-acting, and tolerance can develop. So, there has been some inconsistency with the results, but overall, however, the benzodiazepines approximately double the risk of an accident. Most of the studies have found that these effects are dose-related and higher, the risk is higher in the elderly population.

The second and last example that I'll give is the drug Zolpidem. The trade name is Ambien. The drug information, it's to treat insomnia. So, it induces sleep. That's the primary effect of it. It's a sedative hypnotic. Peak concentrations occur at about one and a half hours after dose. So, this is when you shouldn't be driving, between one and, say, three or four hours after you actually dose.

In the PDR, it says it may cause drowsiness, dizziness, fatigue and so on, and again it states -- the manufacturer states cautions against activities requiring complete mental or alertness or motor coordination and again warnings against the combined use of other CNS depressants and alcohol.

Laboratory studies. Single hypnotic doses of Zolpidem are likely to cause significant impairment of psychomotor skills for the first four to five hours. A lot of the laboratory studies and driving studies, a lot of them dose the patients up just before bedtime, and the tests were done 10 or 12 hours afterwards, so in the morning, and no residual effects were documented, but still in those first few hours after dosing, it's imperative that the patient does not drive.

And epidemiology studies. The incidence of Zolpidem in drivers is quite low. It's usually one percent or lower, but in a study that I did a couple of years ago, we had about 30 Zolpidem drivers, and consistently, they were erratically driving, going over the center line. They had slurred speech, slow movements, confusion, poor balance and coordination. They performed very poorly on the field sobriety tests, the walk and turn, the touch the nose and things like that.

And as a closing comment, I'd like to say even though on the bottle or the drug manufacturers may say that you should take Zolpidem before going to bed, a lot of the driving cases that we looked at had actually taken Zolpidem during the day, and they hadn't just taken one tablet, they had taken two or three tablets. So, they're not following the physician's recommendations, and then they're getting in their car and causing accidents.

Thank you.

DR. GALSON: Thank you very much.

Our next speaker is Wayne Jeffery, who's with the Toxicology Services at the Royal Community Mounted Police Forensic Laboratory in Vancouver, Canada.

Welcome.

MR. JEFFERY: Thank you for being here.

The data that I'm going to present today is data from all the forensic labs in Canada, and the specific research project which was conducted in the Province of British Columbia, where we looked at every fatal motor vehicle accident for a cause; that is, we looked at the driver record, the police record, and the weather record, and then we looked at the drugs and determined if they were the actual cause of the accident.

It was mentioned this morning, the most common causes of drugs which can cause impairment. We had a Toxicology Meeting in Seattle two years ago with toxicologists, in which a lot of people got together, and we went through the list of all the pharmacological classes of drugs and said yes, we can come up with classes of drugs which are central nervous system depressants which can cause impairment, and this is the list which was presented.

We also went through the whole class of the DRE Categories Drugs, and what we said with the DRE Program, if you're unaware of it, we can break down impairment into seven different classes of drugs.

The other drugs that we said, cannabis, hallucinogenics, inhalants, Gamma Hydroxy, Butyrate and disassociative anesthetics, I'm going to keep my comments down to the depressant drugs.

These are the drugs which we decided not to include. We said these are the four things which Fiona has already said how do OTCs and RX drugs cause impairment. It's the effect of the drug causes the impairment sedation. Typically, what we've seen in impairment cases, the drug is taken in higher-than-recommended dosage. This causes the impairment. The drug is taken with other medication, and this is also one of the other factors for prescription labeling warning for the combined effects of drugs.

Typically, also, the drug at therapeutic levels is combined with alcohol, and the combined effect causes the impairment.

This is going to be talked about more tomorrow, and I just want to mention it briefly. Europeans have got a classification of drug impairment which goes on pharmaceutical labels, which I'm recommending that we use in Canada. It's a great idea to tell the public how to -- whether this drug is impairing or not. You'll hear more about that tomorrow.

Typically, what I want to do is talk about the drug occurrence in Canadian cases. What we've looked at, we've broken this down into the impaired drivers and the fatals. Typically, with pharmaceuticals, the benzodiazepines are Number 2 in fatals, and I've put these into the groups of drugs, and then the narcotics. The main narcotic we see, of course, is codeine, also causes CNS depression.

Typically, impaired drivers, the ones that we see most often right off the top, are diazepam and nordiazepam, triazolam and lorazepam, with the narcotics in there or the other two drugs. The fifth class of drugs is all of the other classifications together. That's where the antihistamines fit. As Fiona said, the incidence of this is very low.

Typically, the data which I wanted to state out of British Columbia as the important data is looking at all of the fatal motor vehicle accidents in one year. We came to the conclusion that nine percent of all fatals were caused by drugs alone. Fifty percent of these were illicit, 50 percent of these were pharmaceuticals. We had another 11 percent of all fatals were caused by the combined effect of low levels of pharmaceutical drugs and low levels of alcohol. So that again, that goes to the labeling. These are other drugs that we found. THC, other drugs, cocaine.

The impact of sedating drugs. DOT says drowsiness contributes to so many accidents per year and 10,000 fatals each year, Department of Transport. That's Canadian. Canadian study showed that a driver who's killed and has been the cause of the accident is 1.5 more times likely to have taken an antihistamine. That's a Toronto study.

This report says five percent of all drivers may have used antihistamines before driving. CNS depressant effects are common in many OTCs and RX drugs. Typically in the antihistamines, we have three types of antihistamines. The first generation, the sedating. The second generation. Those are thought to be non-sedating at recommended therapeutic doses. The third generation are experimental.

Typically, the conclusion for older generations, these are recognized as sedative effects and are capable of impairing performance to a blood alcohol level equal to about 50 milligram percent or higher. That was mentioned this morning.

The second generation of antihistamines are clearly less sedating and impairing than the predecessors. However, these may produce sedation at two to three times higher than the recommended dosage. The adverse effects of antihistamines may be minimized by time of ingestion, and the risk of an MVA result is inconclusive to negative results.

Conclusion. Patients who took sedating and felt sedating had wore off and was not affecting their driver performance were tested and found to have impaired performance, even though there was no feeling of sedating effects at all. Again, this was mentioned this morning.

Typically, as I mentioned, the benzodiazepines, the cause of benzodiazepine impairment is in the first few days of treatment, combined with alcohol, combined with other drugs, too high a blood level and the type of benzodiazepines.

Typically, as Fiona has already mentioned, it's two to five times the risk of accident in the first two weeks. That's after -- for an accident. The first two weeks of use, the risk is five to 10 times. It was also mentioned this morning that risk drops down to about twice after about a month.

Effects on driving performance and somnolescence and sedation, loss of motor coordination, memory impairment, behavior disinhibition and paradoxical agitation. This is the most solidly-documented evidence with regards to impaired driving.

Typically, the barbiturates are not widely prescribed anymore, but typically these are equivalent to a BAC of greater than a hundred milligram percent. We deal with the properties of the antidepressants. It's been broken down to the no sedation, minor sedation, moderate sedation, and severe sedation. These are recommendations from the toxicologists.

Stimulant drugs. We won't deal with opiates at all, as I said. Typically, there's no significant impairment during methadone maintenance therapy. However, in high doses, there is lots of abuse of that, and also in Canada, we see lots of abuse of codeine because it is legal, and we have lots of abuse of it, of the Tylenol 3s.

Effects on driving of sedation. Impairment of cognitive functions, mood changes, impairment of psychomotor functions, and typically, these wear off after some days or weeks.

Required medication. There are certain required medications, specifically the anti-convulsants, that also may cause impairment. Typically, I want to mention one thing. Being a pharmacist, also, the important thing for prescription labeling -- and I know this is for tomorrow, but I won't be here tomorrow, so I want to get my two cents worth in.

Specifically interaction with alcohol, specifically driving impairment, drug interaction, and side effects, these should almost be mandatory labeling for specific classes of drugs which we've talked about which cause impairment, and again those are the things I have to say.

DR. GALSON: Thank you very much.

Our next speaker is Judy Stevens from the National Center for Injury Prevention and Control, the Division of Unintentional Injury Prevention, at the Centers for Disease Control and Prevention, in Atlanta.

MS. STEVENS: Thank you, and I'm glad to be here today.

What I'll be talking about briefly is what epidemiology can tell us about medications and driving impairment. There's a longstanding concern that commonly-used psychoactive medications, such as sedatives and tranquilizers, may impair driving ability.

Today, I'm going to be focusing on the evidence provided by a number of population-based epidemiological studies that examined the association between medications and traffic crashes.

Unlike small-scale clinical studies, these epidemiologic studies use data from large populations and assess the public health effect of medication use on driving safety. These studies estimate the relative risk of motor vehicle crashes associated with certain types of medications while adjusting to factors that might affect the relationship between driving and medication use, such as age, previous medical care, and health status.

Based on epidemiology, what do we currently know about this problem? Between 1990 and 1998, there were six large population-based epidemiologic studies published that examined the association between medication and traffic crashes. The majority, four of six, only included drivers aged 65 and older, while two included drivers of all ages. These studies used databases that linked Medicare or other large health care databases with emergency or hospital records, pharmacy and prescription data, drivers license records and motor vehicle crash reports.

The studies looked at a limited number of psychoactive drugs. All six studies included benzodiazepines. Three studies also included six antidepressants, two included oral opiates, and one included selective serotonin and reuptake inhibitor antidepressants.

Over time, the studies have defined medications more precisely. For example, while five studies looked at benzodiazepines as a group, two more recent studies also assessed long- and short-acting benzodiazepines separately. Two studies divided benzodiazepines into sedative hypnotics that are prescribed for insomnia, and anxiolytics that are prescribed to alleve anxiety. Three studies included dose response effects. Two compared risks for short- versus long-term use, and two compared crash risk to long- and short-acting benzodiazepines.

To summarize the results of these studies, despite study limitations, evidence from this research suggests that benzodiazepines do increase crash risk as much as 50 percent, and this risk increases with increasing dose or with taking more than one benzodiazepine.

Two studies suggest that this risk drops with continued use. The majority of the risks may be with the long-acting drugs. With the short-acting medications, crash risk seems to be highest during the first week or two of therapy. Among the benzodiazepines, hypnotics that are taken at night appear to pose less risk than the anxiolytics that are usually taken during the day.

A limited number of studies provide less convincing evidence about other drugs. Results from only two studies of older adults suggest that different antidepressants may double crash risks while oral opiates and antihistamines do not increase risk, but there's still a great deal we need to know about this issue.

In order to accurately estimate risk, we need to precisely determine exposure. Many psychoactive drugs are prescribed on an as-needed basis. So, studies using records and dates of prescriptions may not accurately reflect use. Other drugs, like antihistamines, are available over-the-counter. So, it's difficult to get accurate information about use.

Unlike alcohol, we cannot use blood levels of drugs that affect soluble measures of impairment. We need better ways to ascertain what drug or drugs are taken, at what time of day, at what dosage, and then to link this information with data on motor vehicle crashes.

We need to conduct additional epidemiologic studies of benzodiazepines to clarify the differences in risks for long- and short-acting medications, to study the risks associated with hypnotic and anxiolytic benzodiazepines and to look at risks for short- and long-term use of these drugs.

We need further study of antidepressants among people of all ages, and we need to study additional prescription and over-the-counter medications that may impair drivers, such as codeine cough medicines and antihistamines, and see if these medications also contribute to an increased risk of motor vehicle crashes.

Studies need to be broad to include drivers of all ages and to assess whether alcohol in combination with some medications is a significant factor, and to take into account the metabolic effects of aging on drug metabolism and on tolerance.

We need to know whether impairment differs by gender. We need to understand whether long-term use of some medications increases or decreases risks, and we need to learn more about conditions, such as depression, that may influence the relationship between driving ability and the likelihood of taking medications.

To answer these questions, we will need to develop more complete and complex databases. We'll also need to develop new and creative approaches to obtaining detailed information about the use of prescription and non-prescription medications that may be impairing drivers, and finally, this information needs to linked to comprehensive data about motor vehicle crashes.

So, in summary, these population-based epidemiologic studies have provided us with basic information about the risks of traffic crashes associated with benzodiazepines. However, further research is needed to provide clear and comprehensive answers about the impact of all types of medications on transportation safety in the United States.

Thank you.

DR. GALSON: Thank you very much.

Our last speaker on this panel is Douglas Lamar Allen from the Alcohol and Drug Program Management of the Federal Rail Administration.

Welcome.

MR. ALLEN: Thank you very much.

As mentioned, I am from the Federal Rail Administration, but since we're one DOT, we're interchangeable. So, I'm speaking from FRA for the entire DOT about some of the data that we have available to us to review this particular issue.

This first slide, even though it's pretty busy, I thought I would throw it up here so that everybody could review it, reflects our post-accident testing program since we started it in 1986 with the first data coming in in 1987.

Everybody understands the years and that goes down through about two weeks ago in 2001. The events mean -- this, of course, is not all the times that we put a wheel on the ground in the rail industry, but it reflects essentially non-fender benders, most of the events that are required to be tested for under our regulations.

The other column reflects the number of safety-sensitive employees tested after one of these events per the regulation, and then the last and most important column is the number of positives, and you can see that it is descending the way we would want it to with the programs that we have to address illegal and in many cases in our program legal drug abuse.

Now, these are positives. I do need to caution you that these are identified as drug or alcohol present. It does not indicate a causal relationship, and, of course, the D stands for drugs and the A stands for alcohol.

This particular data reflects 1,717 events in the last 14 years, where we had almost 6,000 railroad employees tested for seven drugs and alcohol. Specimens taken for analysis were urine, blood, tissues in fatalities, and a review of the cases with positive drug test results indicated to us the following: that from this six-year time frame that we have here, that was the non-archived data that I had available to me to review for this particular meeting, we had 460 qualifying events, and believe it or not, it came out right on 1,200. I was hoping it would come out a little different. I didn't fudge the figures. It's 1,200 personnel.

The results were 16 cases involving non-authorized drug use and 27 cases involving authorized drug use. I'll discuss that further. Cases involving unauthorized drug use, illegal drugs, if you would, marijuana, eight cases. It was a total of 12 in this particular arena. Eight cases with marijuana and four cases of cocaine.

Now, legal drugs, if you would. We had two cases that were identified for amps and one for -- excuse me -- two for barbs. Now, these are cases involving authorized drug use, authorized prescriptions used while on duty. We had eight cases, broke down as follows, as you can see here, four cases for benzos, two for amps, and two for codeine.

Now, in these particular review of the circumstances of why these individuals were -- had these in their system and whether or not they were authorized per our regulations, in all cases, we found that they had been authorized by a dispensing physician with the knowledge that this person was doing a safety-sensitive duty in the rail industry. So, that's why we call that an authorized use per the regulations.

The next bullet, medications administered after the event, of course, this stands on its own here, that these medications that we found in our post-accident tox testing really had nothing to do with the event itself.

Now, I looked at a couple other studies from the FAA perspective. They have been tracking crash autopsy results for general aviation, this is not commercial specific, it's general aviation pilots for years.

In a study conducted by CAMI from '94 to '98 on all fatal crashes, there was 1,683 pilots tested for at least 58 different drugs. We say 58 because that's what we identified, 58 different classes were found. I don't know exactly how many they tested for.

Over-the-counter drugs present was in 301 cases, 18 percent, prescription drugs presence, 240 or 14 percent. Dose levels in this particular study was not reported, so therefore it could be insignificant and/or non-impairing, and also the study did not identify any linkage to the accident causal factors either.

Now, this data gives us some trend data to look at to establish for our policies the risk, so that we can appropriately address the policies that we have in the DOT, and in final conclusion, the rail data that we've looked at, there were only four cases or .33 percent involved unauthorized use of over-the-counter or prescription drugs, and the review of cases even on those indicated other factors were the principal cause of the event. Even though they had these drugs in their system, that drug did not cause that rail to break and so forth.

In general aviation, we surmised that the higher prevalence was due in part to larger samples of drugs analyzed and also that the population that was reviewed here was general aviation as opposed to commercial operators, and they are under a different umbrella, if you would, of deterrence and programs that applied to them.

That's all I have. Thank you.

DR. GALSON: Thank you very much.

We're now going to move to have questions of the panel, first from the -- questions of the witnesses from the Technical Panel, and we'll start off with FDA, Mr. Meyer.

Questions from Technical Panel/Parties and Discussion

DR. MEYER: First of all, thank you all for your presentations.

One of the problems that we often have in assessing causality for adverse events that we see is something called "confounding by indication". Basically, the fact that the adverse event may be itself related to the disease rather than the drug, and I'm curious.

I know Dr. O'Hanlon had mentioned some limited indications where he did not find evidence of baseline driving impairment, but to use a very perhaps hyperbolic example but one that's perhaps not wholly theoretic, if you had a single car accident, for instance, the person drives into a tree, no skid marks, he's on a tricyclic antidepressant, could be that he fell asleep due to sedating properties of the drug. It could be a suicide, and that's again a hyperbolic example, but there are a lot of issues of what, again from an epidemiologic standpoint, is called confounding by indication.

Are any of the panelists aware of attempts to try to tease out in assessing causality or potential causality of these drugs in the accidents, the indication versus the drug effect itself?

DR. COUPER: I'll try and briefly answer that. I briefly mentioned a group down in Australia, Melbourne, Associate Professor Olive Drummer and colleagues. They did some culpability studies. They've been doing it over the last six years, and they're really nice studies.

They work at the Victorian Institute of Forensic Medicine, and so what they've done in the last -- I think they've looked at about 3,000 fatalities, and they cooperate with the police, so they get the full police reports. They try and get weather conditions, the conditions of the car, eyewitnesses, all sorts of things, blood results.

They interview the family members to see whether there were suicide intentions or things like that. So, they've tried to do that. They've tried to answer that question, and then if there's a single drug involved or multiple drugs involved, and whether they think that drug either caused or contributed or had no effect to the actual accident or the fatality.

But I do agree with you, just because someone's crashed into a tree, you don't know whether they were using their cell phone and were distracted, a spider came down, and they just ran off the road or actually it was because they've actually fallen asleep or taken their eyes off the road.

MR. JEFFERY: In the data from the BC, we looked at the driver accident record, the police record accident, and the medical -- and comments from the coroner and interviewed the family. So, a lot of that data can be flushed out, and typically in the coroner's reports for the investigation, it depends upon their role and how far they're going to go into investigating that accident.

But typically in our study, what I looked at, we looked at the blood level and did -- looked at the level to see whether it was a therapeutic, toxic or a much higher level, and you could get some indication from that.

MS. STEVENS: Looking at some of the population-based studies, there have been a few that have tried to control for the presence of chronic diseases to try to rule that out as a contributing factor, and that data is difficult to get, but that attempt -- it's important to be able to adjust for the presence of other chronic diseases to try to get at why the medication was in use.

DR. MEYER: Again, maybe I was unfortunate in the example of hitting the tree, but, you know, insomnia, for instance, is in itself a cause of day-time hypersomnolecence and, you know, altered sleep latency. So, I think that confounds the interpretation of the results of benzodiazepines taken as sleep aids, for instance.

Again, you know, you could do this with other indications, but it strikes me as an issue in interpreting these data where causality is not so -- it may make a lot of sense, but it's not entirely clear from an epidemiologic standpoint.

DR. TEMPLE: Dr. Stevens, could you say something about -- a little more about the design of the six studies you were referring to?

These weren't cases -- these were sort of cohort studies, I guess, not case control or just what was the design, and how good do you think they are?

MS. STEVENS: Well, it varied. In some cohort studies, there was a domestic case control study within a cohort study. I have those copies of those citations, if you'd like to see them.

DR. TEMPLE: Well, I'm sure we would. We would like to be sure we have them.

MS. STEVENS: Most of the medication information did come from records, and they were prescriptions, you know, numbers of prescriptions that were filled, that sort of thing. So, knowing whether people actually had taken the medication was implied rather than actually known.

You want the whole study designs specifically? Is that what you're asking?

DR. TEMPLE: Well, just some sense about how solid this is. We've heard about individual cases that on their face look as though something was going on and that surely is one approach, but for a more quantitative, how big is this problem kind of look, it seems to me you need something like the studies you're talking about.

MS. STEVENS: Most of these were retrospective cohort studies. Most were quite large, which I think is important if you're trying to get a sense of the problem. It's a little hard to summarize six studies in terms of design when they're all a little bit different.

DR. GALSON: Yes. I'm not sure we can take up the time to go into the detail right now, but it would be very important if you could make sure to perhaps have a copy of your remarks and the studies that you're referring to, either the references or the actual studies, that would be real helpful for us as time moves on.

MS. STEVENS: Yes.

DR. GALSON: Thanks. Does NTSB want to have a question now?

DR. GARBER: Yes. I'd like to pose a question of the DOT representative, Mr. Allen.

I think I noticed in your last slide that you said the FRA found incidence of only four cases of prescription or over-the-counter medications that were in any way related to the accidents.

I'm curious as to what over-the-counter medications the FRA is testing for.

MR. ALLEN: Well, we have the capability to test for pretty much anything in our laboratory. So, if we had an indication through our accident investigation that this person was taking anything, we would work up a protocol to look for that.

We don't go and look for everything in the PDR for obvious reasons. We look for the standard eight, if you would, that we look for, which is essentially the NIDA-5 plus barbs and benzos and alcohol.

I think I put this on here because of the context of the meeting here today, that we're talking about over-the-counter and prescription drugs.

DR. GARBER: Okay. But just so that we're clear, the FRA does not routinely test for over-the-counter medications?

MR. ALLEN: No, sir, we do not.

DR. GARBER: And so, you routinely test for eight different substances?

MR. ALLEN: That's correct.

DR. GARBER: Of which two are prescription medications? The benzodiazepines and the barbiturates, potentially amphetamines as well?

MR. ALLEN: Amphetamines and opiates, too.

DR. GARBER: Right. Is the opiate testing done -- is that done in accordance with DOT guidelines or is that separate from those guidelines?

MR. ALLEN: Our protocols at our laboratory are -- follow closely to the DOT, but we go -- our cut-off levels are lower and so forth because we do have different mediums to look at with the blood and the tissue.

DR. GARBER: The only reason I ask that is that the DOT guidelines are -- it often is difficult to detect some of the synthetic opiates, the hydrocodones and those type of opiates, with using those particular testing guidelines. Is that -- are those --

MR. ALLEN: That's not a problem for us.

DR. GARBER: Okay. And you noted that 18 percent of the fatal pilots tested for by the FAA did have over-the-counter medications in their system, although it wasn't -- there was no relation to the cause of the accidents from those data.

Does that suggest that it may be useful for the DOT or anyone else, for that matter, to be looking for those drugs to make that determination?

MR. ALLEN: Well, once again, I draw your attention to the scope of this testing by the FAA was not commercial testing commercial pilots. This was general aviation pilots. So, we don't have anything to go one-for-one with the Department of Transportation's scope that it works with with commercial aviation.

DR. GARBER: But just for a frame of reference, you said 18 percent had over-the-counter medications. How many had alcohol detected?

MR. ALLEN: I don't know that off the top of my head.

DR. GARBER: Okay.

MR. ALLEN: I don't have that.

DR. GARBER: Okay. And just one question for the entire panel. A witness in our last panel indicated that sedating antihistamines were probably not a large problem with regard to transportation safety, based at least somewhat on the adverse experience reporting, and I'd just like to ask each of the panelists just very briefly.

Do you agree with that assessment, that the sedating antihistamines are likely not a problem, based on adverse event experience reporting?

MR. JEFFERY: In the BC data, we only had one fatal motor vehicle accident caused by the antihistamines, and yes, I'd agree with them. I mean, on the scale of impairing drugs, it's at the lower level. There are other drugs that we're more interested in, yes.

DR. GARBER: Any of the other --

DR. COUPER: I would essentially agree with that. The cases, though, that we've seen with the sedating antihistamines, diphenhydramine for example, the people are taking them in huge amounts. They're not therapeutic doses at all. Just the toxicology, the blood results in and of themselves must mean that they're taking way above the therapeutic levels.

So, in that regard, yes, they are probably very sedating, but normal therapeutic doses, no, we're not seeing those in our cases.

MS. STEVENS: Most of the epidemiologic studies that have tried to look at these were looking at only the prescribed antihistamines, and there is really no way of knowing whether people were taking over-the-counter medications from the records. So, that really is something that needs to be looked at, I think, a little bit further.

MR. ALLEN: I would have to say the same thing because we're, as you just pointed out, looking for the prescribed medications as opposed to the over-the-counter, and the data reflects that we have not found it in our reviews.

DR. TEMPLE: The last two answers say there's no information. The first two suggest that there was no finding. Can I ask you about those? These are mostly cases where, for example, Dr. Jeffery, the cases where the driver was doing something bizarre and that's what would be triggered.

Suppose the person just fell asleep. Would you have any information about something like that?

MR. JEFFERY: Yes. Well, the one case that we had, that was the actual case, where the driver actually fell asleep and went into the tree, but the level of antihistamine we found was way high above the therapeutic. So, we could only conclude from that that it was the antihistamine.

In a lot of these situations, we have to go back to see what we did with alcohol with fatal motor vehicle accidents, how we came up with 80 milligram percent. We did a whole bunch of studies, found 80 milligram percent was sort of the cut-off level. That's how we made our impairing level, and what we're doing right now is we're back at that same level with regards to drugs.

There's a committee of toxicologists looking at this data right now, saying can we come up with blood levels of drugs that are impairing? Twenty years ago, you'd get a bunch of toxicologists in the room saying no, we can't do that. However, we have now come to the point that we may be able to do that for some drugs and that's what we're looking at right now.

DR. TEMPLE: But the way you would do it would be to look at fatalities and see what's there?

MR. JEFFERY: Yes.

DR. TEMPLE: And then compare that with some estimate of what would be there in a normal population?

MR. JEFFERY: Absolutely.

DR. GALSON: Okay. I think what we'll do now is move to the Questions from the Parties at the table, and I want to just take the opportunity to instruct the audience, if you have questions, please think of them and pick up a card from Lee Lemley standing at the back and then she'll pass it up to us.

I noticed there are a few new people sitting at the tables. So, can we quickly go around and have those of you that are new just introduce yourselves and say where you're from?

DR. TILTON: My name's Dr. Fred Tilton. I'm the Deputy Federal Air Surgeon, FAA.

DR. GALSON: Great. Welcome. And then at the Union Table, there's somebody new.

MS. HEAD: My name's Karen Head. I'm with the Amalgamated Transit Union.

DR. GALSON: Okay. Welcome.

MR. BRADLEY: My name is Bill Bradley. I'm with the Consumer Healthcare Products Association.

DR. GALSON: Okay. Why don't we this time start from the Government Table, and let's see if you folks have any questions for the panel.

MR. CLARKE: I don't. No, I don't have any questions. I thought the presentations stood on their own.

DR. GALSON: Okay. The Professional Panel, the sleep experts, in the back there, anything?

(No response)

DR. GALSON: Okay. Advocacy?

MS. TARNEY: We have several questions.

DR. GALSON: Okay.

MS. TARNEY: Well, we'll start with a comment, which is, that it's difficult to compare different accident studies for accidents due to non-standardization. In other words, different analytical nanograms, no. The cut-offs don't have them, whether you're using blood or urine, also changes the outcomes.

The rest of the calculations, similar to what has been done for alcohol, makes it difficult due to the drug use among what may be a normal population and then that's not known.

So, I guess the question is, what is the standardization for accident studies? The comment was, well, the standardization of accident studies is necessary in the toxicological arena as well. Can anybody tell us how we can standardize it from a toxicological standpoint? That's one question we had at our table. We have some more.

MR. JEFFERY: Well, in the one study that I've done, what you've got to look at is you've got to try to rule out everything else, environmental factors, weather, driving pattern, the whole bit to deal with did the drug cause the accident, and this is the data now that all the toxicologists are trying to put together, and it's hard to standardize that because each laboratory in Canada is slightly different. Each state is totally different.

It's the constraints of what we can do, but the more data we get, the better it's going to be. So, I think it would be very hard to standardize that collection of data.

MS. TARNEY: How do you see the variety of things being tested right now, such as hair, saliva, as well as blood and urine in terms of standardization and reliability?

DR. COUPER: I think Wayne Jeffery can probably talk about the saliva but just on the hair issue, it's not really a relevant tissue in this scenario because hair is an indicator of past exposure to a drug, whether it was a week ago, a month ago.

If you tested my hair, it was probably a year ago. So, if you're talking about the effects of the drug, you're talking about the drug that's in your body within the last three or four hours or five hours, however long. So, hair testing probably isn't relevant, but a lot of saliva testing is being done.

MR. JEFFERY: Yes. Actually, as a toxicologist, blood is probably the preferable sample. I mean, that's the level of drug which is causing the impairing level.

Urine is the second best one for toxicologists to look at previous drug usage, but a study which I'll be publishing very soon is on saliva shows very good correlation to impairing results in the study with our drug recognition expert officers in British Columbia.

So, saliva is a very good thing to show recent usage of a drug use. So, I mean, blood is best, and from our point of view, however with laws and that, you may not be able to get it. I think saliva is a very good second substitute.

MS. STEVENS: I think it's important to remember that if a drug is fat soluble, the blood level and level of impairment may not be that tightly correlated, especially when we compare alcohol, where you can look at the blood alcohol level and have a very good idea of what the impairment is.

MR. ALLEN: In the FRA, we have found that having all the mediums possible really helps our analysis of the situation.

We have been able to use encapsulated parts of the body and, of course, tissue samples to rule out other findings in other parts of the body. So, adding all the different possibilities that your rules and regulations will allow you to harvest in an accident investigation situation has been very valuable for us.

MS. TARNEY: Based on the variety of medications that people take, how do you deviate from normal in a blood sample for impairment?

MR. JEFFERY: Could you repeat that question?

DR. COUPER: Or maybe rephrase at least.

MS. TARNEY: Based on the combinations, the many combinations of drugs that people take, how do you compare that to what is normal, which also has a variety of -- a wide range of indicators? What is your deviation for impairment?

I think that's one of the questions that people have about using blood or urine or saliva samples.

MR. JEFFERY: Well, typically, when we analyze a blood sample, we'll analyze from the drugs which are there. We'll not only do a qualitative identification of what drug is present but really how much is there, and that's what we look at in a blood sample. If there's two or three drugs at very low levels, we have to make an opinion, are there additive or what are the effects going to be, and we have to make -- the toxicologist will make a subjective decision in saying are the combined effects of these drugs impairing or are they not impairing, and that's where our training and experience comes through in the blood databases that are published on whether these drugs are therapeutic or toxic.

MS. STEVENS: I think it's also something that gets into what was covered this morning, is that standards of impairment, measuring impairment, need to go beyond simply the biological measurement, so that there is some correlation, and we haven't really gotten there yet.

DR. GALSON: Okay. The Carrier Industry Table, do you folks have any questions for the panel?

DR. FAULKNER: No questions.

DR. GALSON: No. Consumer Product Industry, any questions?

DR. SOLLER: Yes, just a clarifying question to Dr. Stevens. Just given the extensive use of RX antihistamines and in consideration of our AER analysis that we showed this morning where we looked at RX and OTC antihistamines, didn't Ray et al. study a cohort of more than 16,000 Medicaid elderly, finding that the relative risk of injurious crash accidents was not a matter of concern? I think it was a relative risk of around one, something like that.

MS. STEVENS: Yes, that's correct. However, he was only one of only two studies that have looked at antihistamines in the population. That's my concern, is that there's been so little, but he had a very thorough assessment of people taking that because everything was covered.

DR. SOLLER: I just only was clarifying in relation to a prior question. Yes, thank you.

MS. STEVENS: You're absolutely correct.

DR. SOLLER: Thank you.

DR. GALSON: Does the Union have any questions?

CAPTAIN POPIEL: No questions.

DR. GALSON: Okay. I think we'll cycle back to the Technical Panel. Does NTSB have anything further?

DR. GARBER: Just one point of clarification for Mr. Jeffery. I believe that you had mentioned a study that showed a 1.5 times increased risk for antihistamines.

MR. JEFFERY: Yes.

DR. GARBER: Could you give us a little bit more detail on that particular study and the numbers involved?

MR. JEFFERY: That was a study out of Saskatchewan, I believe, and they looked at all of the population in the province of how many prescriptions were given for antihistamines in different areas, then went back to those people and looked at their driver records. This is an older study that came back in the late '70s or early '80s. They were looking at just not a few hundred, it was a few thousand people involved.

DR. GARBER: So, this was a fairly robust study that showed a 1.5 times increased risk for the antihistamines?

MR. JEFFERY: Yes. I can give you that citation.

DR. GARBER: Okay. And based on the -- perhaps you can comment more on Canada. Based on the use of these antihistamines currently in Canada, and again I just want to clarify your previous answer, you feel that that's not a significant risk, even though -- even with the potentially large population that's using those medications?

MR. JEFFERY: Well, you know, on the scale of one to 100, I mean, antihistamines are at the lower level. If you take a look at the benzodiazepines, which are widely prescribed, also, they're much higher. I mean, yes, it is a significant risk, but it's on the whole level, it's a much lower risk.

DR. GARBER: Are the antihistamines available over the counter in Canada as they are here in the United States?

MR. JEFFERY: Oh, yes, absolutely.

DR. GARBER: Do you have a feel for what the level of those prescriptions are vis a vis benzodiazepines?

MR. JEFFERY: Oh, the over-the-counter ones by themselves are used far more widely than the prescription drugs.

DR. GARBER: Okay.

DR. TEMPLE: The Saskatchewan study captured prescription and non-prescription?

MR. JEFFERY: Yes. It was through the whole area of prescription and non-prescription.

DR. TEMPLE: And what about Wayne Ray's study? That must have linked to a Medicaid database or something.

MS. STEVENS: It did. It was just among people 65 and older. So, the Medicaid enrollees basically got all of their medications through that system, and so --

DR. TEMPLE: Including OTC?

MS. STEVENS: -- those were captured. Hmm?

DR. TEMPLE: Including OTC? So, he would have captured that?

MS. STEVENS: He would have captured those, though they could have gotten them, you know, outside of that system. Very few do.

DR. GARBER: Just a question for each of the panelists. In an ideal world and recognizing, of course, that we don't live in such a world, how would we go about -- what would give us the data? What specifically would give us the data that we need to make a determination from an epidemiologic standpoint on whether these drugs are problematic in the same way -- in the same sense that, say, alcohol or any other issues are problematic?

And then, as a follow-on to that, can we do that? Can we? Do we have the capability of doing that?

MR. JEFFERY: Well, I think for alcohol, that was done by the Grand Rapids Study, where they went through and took samples from the public where accidents occurred. It was done over a certain amount of time. That was easy to do with regards to alcohol, and if you want to get the actual role of drugs in driving in the normal population, you would basically have to duplicate the Grand Rapids Study.

DR. COUPER: And that probably couldn't be done for most of the drugs because the Grand Rapids Study, I think, was based on breath alcohol levels. So, you weren't being -- it wasn't an invasive blood test or a urine test. So, it was easy to do the breath test, and I doubt that here in America, you'd ever get that number of people. There were thousands of people giving blood samples.

DR. GARBER: So, am I correct in interpreting your answers, that it may not be possible to either include or exclude drugs definitively in the way that alcohol was by such a study?

MR. JEFFERY: You could do it on a lower extent. There's just a recent study published out of Montreal, from the Forensic Laboratory there, where they took random saliva samples and urine samples from drivers in the known public, and they were looking at about one to two percent of the population that had these drugs on board and whether there were accidents involved and whether they were charged with impaired driving or some type of other offense. So, I mean, it's going to be very, very difficult to do that.

DR. GALSON: Okay. I think -- I'm sorry.

DR. TEMPLE: What do you think of the following possibility, and, of course, I'm also interested in who you think might be willing to do it; that is, to get blood samples from people -- this sounds bloody, but I'm sorry. People in fatal crashes and compare the blood content of the driver and the passenger as a possible indicator of an increased risk?

MR. JEFFERY: Well, that's the study that we actually did in BC. We took blood samples from every one of the fatal motor vehicle accidents, and typically in Canada, I can speak, that that is not routinely done. That is only routinely done whether there's an investigation if they think alcohol or drugs is involved.

Alcohol is done on a routine basis. Drugs is only done on one to two percent, and you may get a lot of data involved if you had every fatal motor vehicle driver killed within a certain period of time. If samples were taken from that driver and analyzed, you would get, over a two-or-three-year basis, a good data bank with regards to what drugs are there.

I think some of the studies that have been produced already in Australia and my study in BC and the ones in the States and in Europe start to show, I think, the levels of drugs which are already there, and I think we have a good handle on that, but it would give you a far more better understanding of what drugs are involved in driving fatalities.

DR. TEMPLE: And perhaps you've already answered this, but do you think there have been enough studies of that type to finger benzodiazepines as a problem? Do you think there is enough data yet on potentially sedating antihistamines to give an answer one way or the other?

MR. JEFFERY: Basically, absolutely. I mean, we've got enough data for benzodiazepines. We have enough data now to show that we're not seeing therapeutic levels of sedating antihistamines in fatal motor vehicle accidents or in the impaired driving cases. There are very low levels of less than one percent.

MS. STEVENS: I think if we want to look at whether there's an increase in risk, you have to have a comparison group beyond the people who are dying in motor vehicle crashes.

DR. TEMPLE: That's why I like the passengers.

MS. STEVENS: Well, they're also involved. I think that there's probably more likely a correlation between the driver and the passenger. You need to look at it in the population as a whole.

DR. TEMPLE: But before you leave that, that seems logical for alcohol or an abused drug. It doesn't seem equally likely for, say, an antihistamine, does it?

MS. STEVENS: Well, if you've got two family members, everyone knows that colds go back and forth, and it's possible, I think there's probably some similarities there that couldn't be written off. So, it might be a long shot.

DR. COUPER: If I could make a couple of comments to the last two questions? The first question about the passengers, the study that I mentioned, the culpability study done in Australia by Drummer, and I'll try and get you some references for that, it really was a good study.

They did a comprehensive blood test, urine test, vitreous, liver, kidney, a whole lot of samples from the fatalities. It wasn't only from the drivers, it was any passenger in the car or any pedestrian that was hit by a car. So, any road fatalities, they've done that, and they also used a control group as well. So, that could be a nice study for you.

Whether -- one of the problems with us toxicologists is a lot of the states have a lot of these data. I know in Washington State, we do comprehensive drug testing on a lot of the fatalities. So, it's not just blood, it's blood and urine. We don't just do alcohol and a drug screen, we go further. We look for the over-the-counter and prescription medications.

The problem with the toxicologist is we haven't published these data. So, the data is probably out there in many of the states here and in Canada and probably the rest of the world, but a lot of us just don't publish that results.

DR. GALSON: Okay. I think we'll turn now to some audience questions. If we have extra time, we'll go back to the panel again.

DR. ELLINGSTAD: Okay. We have four submissions here. One question, I guess it's addressed to NTSB. Would NTSB like to see the DOT establish a regimen for conducting post-accident or other types of testing?

I believe the record does show that the NTSB would like the Department of Transportation to do that. We're waiting for them, of course, to respond.

We have also a question for Dr. Jeffery. Would you care to speculate on opiate prevalence data in Canada versus the United States related to legal and over-the-counter availability in Canada but not in the U.S.?

MR. JEFFERY: Well, in Canada, what we have is Tylenol Number 1, which is eight milligrams, which is over-the-counter. In the data that we see, and the Number 1 drug of abuse abused in BC right now is Tylenol Number 3, which is the 30 milligrams of codeine.

In the impaired drivers in the fatal motor vehicle accidents, that is the fourth class of drug we see, and in the narcotic group, codeine far outweighs all of the other narcotics.

In Vancouver, we have a huge heroin problem. We don't see that. It's the over-the-counter of codeine tablets and the Tylenol Number 3 which are the major problems for the narcotics.

DR. ELLINGSTAD: Any of the other panelists wish to comment on what one would expect in the United States?

(No response)

DR. ELLINGSTAD: We have another question that I believe was intended for Mr. Allen regarding FAA studies from consecutive four-year periods which showed the incidence of different kinds of drugs in fatal crashes among, I presume, general aviation pilots. Are you familiar with that research?

MR. ALLEN: I know of the research. Dr. Tilton or Bob Clarke may be able to -- I don't have the study with me, but it's available, and we'd be glad to give that to whoever.

DR. ELLINGSTAD: Okay. If we could have that data or have those studies, the citations for the record?

MR. ALLEN: We'll provide them.

DR. ELLINGSTAD: If I might add one question? We had -- we've been talking about various kinds of ways of establishing the incidence epidemiologically. Dr. O'Hanlon this morning reminded us of the Borgenstein Grand Rapids Study that basically provided that kind of an indication of incidence with respect to alcohol.

Just very quickly, is there any kind of an analog to that with respect to any of the medications we're talking about?

MR. JEFFERY: Not that I'm aware of.

MS. STEVENS: There's very little with the incidence of medication use in populations. Some of the studies have looked at limited number, but they are either looking at medical prescription records or they ask people, you know, what they've taken which gets into a recall problem.

DR. ELLINGSTAD: Is this something that's affected by the comprehensiveness of testing in the various transportation modes or are we testing enough to accomplish that kind of empirical basis?

MS. STEVENS: Well, if you're looking to get the information about medication use in the population, you would have to be testing populations, not simply the people who are involved in the fatal crashes. I don't think that that's a practical approach. So, it would be indirect through prescription records and face-to-face interviews would be the way that I would see you'd have to get that information.

DR. ELLINGSTAD: Thank you.

DR. GALSON: Okay. Nearing the end of this session. Does the Technical Panel have some more points they want to ask?

DR. GARBER: I just did want to mention that Mr. Allen mentioned the comprehensive FAA toxicology evaluation that's performed on general aviation -- fatally-injured general aviation pilots.

The NTSB reviewed those data and uses those

-- we use those in our accident investigation evaluation, much in the same way that Mr. Jeffery and Dr. Couper have described for the studies that they have done.

In our review of recent data from that, we find that over-the-counter prescription medications to be factors in the accidents more often than we find either alcohol or illicit substances to be factors in those general aviation accidents.

I'm curious as to whether (1) that sort of comparison has been done with the data that you have, and (2) whether that surprises any of the panelists, whether that seems consistent with the information that you've seen through the studies that you've either done or reviewed.

MS. STEVENS: Well, I wonder if, since we learned to drive at an early age and we drive for so long, if driving as a skill isn't quite different from the skill that's needed as a pilot, and so that we could compensate for a lot of impairments with our driving that may not be possible when flying a plane.

DR. GARBER: Any comments from any of the other panelists?

MR. JEFFERY: Well, typically what we're seeing in the impaired drivers in the fatal motor vehicle accidents, we're really not seeing just the therapeutic levels. We're seeing high and above those or in the central nervous system depressants, we see the impairment or the fatal motor vehicle accident early on when they've been taking the drug and tolerance hasn't been developed at that time.

MR. ALLEN: Within the FRA program, as you know, Dr. Garber, we share with the NTSB any specimens that we have from fatalities, and we have, to my knowledge, never received anything back from the NTSB giving us any data that would make us be concerned about the other drugs and over-the-counter.

DR. GARBER: I'm sorry. Does that database include the Florida accident? That's one where the NTSB did find evidence of medication use.

MR. ALLEN: I don't know that off the top of my head. I don't know if it was one of the ones that met our criteria.

DR. TEMPLE: This probably is a question that's as much for the previous panel as it is for this one, but let me start here and maybe there's some way for them to comment.

The various tests of driving function that you heard about earlier show levels of impairment similar to blood levels -- that induced by blood levels of alcohol that everyone agrees apparently is a potential cause of accidents, and at least so far in the epidemiology, however, you don't see anything like that in any of the studies that have been done.

Do you have any thoughts about that disconnect or is it a true disconnect? Are there enough data to conclude that there is a disconnect?

I'd also be interested in what some of the previous panel thought about that, if there's a way to elicit that.

MS. STEVENS: Well, the epidemiology studies that I referred to did not take blood measures. These were doses and use was extrapolated from prescription records, so that it would be an apples and oranges kind of comparison, at least for the studies I was talking about.

DR. TEMPLE: Well, but they would be able to see if use of any particular drug was unexpectedly high, and the data we heard earlier in the day are about taking ordinary doses of certain benzodiazepines and sedating antihistamines and finding levels of impairment similar to those that caused trouble when -- similar to those -- finding impairment similar to what levels of alcohol that are known to be a problem cause, and yet when -- from the epidemiology the people have described, there doesn't seem to be an association with the use of these agents or not much of one, I guess with benzodiazepines there is, but not at least the antihistamines.

Are you saying there's a methodological reason or maybe the driving tests really don't predict that? I mean, I just wondered what your thoughts on this were.

MS. STEVENS: I think that getting an estimate of exposure, how much medication people are actually taking through the epidemiologic studies that have been done is very difficult, and there's a lot of possibility of error and not estimating correctly.

So, when you have somebody in a laboratory, and you know what you're giving them, that really is different than looking at it in the population and trying to imply from the records how much you think people were taking and when.

DR. TEMPLE: I think Dr. O'Hanlon might have an answer to this question.

DR. ELLINGSTAD: I think you're going to have to go to a mic. Why don't you come up here to the podium?

DR. O'HANLON: We've studied tripolidine, diphenhydramine, chlorpheniramine. Even after 50 milligrams of diphenhydramine, we saw impairment one hour later, impairment equivalent to .07. It went down pretty quickly with, as you'd expect, from the pharmacokinetic profile of the drug.

We never saw that great a degree of impairment again with another sedating antihistamine. There was some with everyone, but it didn't compare with some of the other antidepressants, some of the mood stabilizers, some of the benzodiazepine hypnotics and anxiolytics we studied.

That's why I remarked this morning what's this big deal about antihistamines, except, of course, that the use is so prevalent. There's no discrepancy, at least in our laboratory, the empirical data agrees quite well with the epidemiological data.

By the way, a couple of comments I'd like to make. There has been one epidemiology study that shows a relationship between industrial accidents and the use of sedating OTC antihistamines. I think it's by Gilmore, but it's an old man's memory now talking, and you can better find it in my former assistant's excellent article on behavioral toxicity. His name is Jon Ramikers, and he published that in CNS Drugs in 1998, I believe. It's a very fine summary of all the epidemiological data published up to that time.

So, there has been one indication from epidemiology that sedating antihistamines can do something, and besides that, Ray did not have access to any sedating antihistamine records and said so in his 1992 article in the American Journal of Epidemiology.

Thank you.

DR. TEMPLE: Before you leave, so, you mean his study didn't --

DR. O'HANLON: Ray's study did not --

DR. TEMPLE: It only included prescriptions which at the time --

DR. O'HANLON: -- include sedating antihistamines. Only one antihistamine was available for the prescription at that time, or a couple of older ones, like hydroxyzine, but the main one was terfenadine. That was the main one that showed up in his Medicaid records.

DR. TEMPLE: I see. So, you're saying that the failure to find anything is --

DR. O'HANLON: In that one case, in that one case, yes.

DR. TEMPLE: Okay. And just to be sure I understood what you said before, you don't find most of them having major levels of impairments, --

DR. O'HANLON: No.

DR. TEMPLE: -- and you're not surprised that nothing much shows up, and even for diphenhydramine, the impairment is relatively short-lived?

DR. O'HANLON: .07. I mean, that's not a good thing.

DR. TEMPLE: Right. And it doesn't last very long. So, it could depend --

DR. O'HANLON: One to three hours, approximately.

DR. ELLINGSTAD: We did have a question from the audience that's directed to Mr. Allen, and basically, the question is, how does the DOT feel about NTSB's recommendation that the Department of Transportation make prescription and over-the-counter drugs part of its testing program?

MR. ALLEN: Well, it is already part of our rules in that we have rules in each one of our modal policies that address that, and speaking for the FRA, we think that our rules and the testing regimen that we have right now within the FRA covers the basis for the risks that we see out there.

I can't really speak for the DOT since, as you mentioned, I think, before, that this is still an open recommendation from the NTSB to the DOT.

DR. GALSON: Okay. A few more minutes, if the Technical Panel wants to ask anything else.

(No response)

DR. GALSON: Okay. Any other questions from the parties?

(No response)

DR. GALSON: Okay. I think with that, then we'll end this second session and have a 15-minute break, which brings us back here at about 2:32-2:33.

(Whereupon, a recess was taken.)

DR. ELLINGSTAD: We'll have a little smaller Witness Panel here, and we'll grill them more exhaustively than we have previously.

I'd again like to remind both the audience and our party participants to generate your questions and pass them and the parties to get their questions to the moderators. Again, with the smaller panel, we'll be more liberal in terms of the questions that we can entertain.

Our third panel consists of representatives from State and Local Government, and we will start out with Mr. William George, Deputy Attorney General from Delaware.

Mr. George?

Witness Panel III - State and Local Government

MR. GEORGE: Good afternoon.

My name is William George, and I am the Deputy Attorney General for the State of Delaware, and for the last 12 years, I've had the sole responsibility for the prosecution of homicide cases arising from motor vehicle accidents, including commercial vehicles.

To address the issues involving the operation of vehicles by those who are drug impaired, I will speak first about the types of laws and regulations that exist at the state level and then about the problems with enforcement of those laws.

In Delaware, we rely mainly, if not exclusively, on our DUI, our Driving Under the Influence, statutes as our primary enforcement tool to restrict transportation operators from operating vehicles while impaired by medications.

Although geared towards and mainly enforced against those who operate a vehicle while under the influence of alcohol, our statute is broad enough to restrict all drugs, both legal and illegal.

Our statute specifically prohibits the driving of a vehicle while under the influence of any drug or under the influence of a combination of alcohol and any drug.

However, the enforcement and the prosecution of the drug impaired driver is very difficult on many levels. The first is detection. For over 25 years now, the states, following the initiative of the Federal Government, have been involved in a process of education, of re-education, and of enforcement that has changed our views on alcohol impaired drivers.

Our police officers, who are our first line of defense in the detection of the impaired driver, are trained in the detection of alcohol. At our academies, new officers are given the opportunity to watch other officers drink alcohol and then gauge their impairment through the use of standardized field tests and the use of an intoxilyzer.

The effects of drug impairment are very subtle, though, and unless the impairment causes the outward and detectable signs usually associated with alcohol impairment, it is possible that the drug impaired driver may go undetected.

Even in those cases where signs of impairment are noticeable, where field tests are given, the officer is likely to hit an impasse when the intoxilyzer displays a 00 reading.

Specific methods of drug detection and documentation do exist, but they are different from that of alcohol cases, and they are beyond the training and expertise of most police officers today.

The second problem is the prosecution of these types of cases. A typical DUI case follows a set pattern during the trial of that case. It begins with the initial observations of the erratic driver by the officer, the stop by the officer, the initial observations of the operator after the stop is made, the establishment of probable cause based on standardized and accepted field tests, and finally the introduction of an intoxilyzer reading or, in rare cases, the introduction of a reading of a blood sample.

In a drug impaired case, the intoxilyzer will not provide adequate evidence, and unless the performance on the field test is so poor, it is unlikely that a conviction could be obtained.

Even in those cases where a blood sample may have been obtained, the quantitative effects of drugs have not been documented or accepted by our courts to the same degree as alcohol has. Similarly, the urine sample is inadequate and unlikely to be accepted into evidence at all.

The detection and prosecution of the drug impaired driver is a problem, but there is a solution. First pioneered by the Los Angeles Police Department with the assistance of NHTSA, the Drug Recognition Evaluation and Classification Program was developed. Its purpose is to determine whether a driver is impaired, and if so, whether the impairment is drug related or medically related and then to determine the broad category of combination of drug categories causing the impairment.

The drug recognition expert or DRE is a specially-trained police officer. The officer is trained not only in the testing usually associated with an alcohol case, but also in medical procedures that include an eye examination, HGN testing, and an analysis of the vital signs of the driver.

Although the DRE program has now expanded far beyond Los Angeles, it is my opinion that it has not expanded far enough or fast enough to address this problem. Certainly the Federal Government can and should take an active role in expanding the kind of training of police officers. The Federal Government should promote the acceptance of these types of programs through education, just as it has actively promoted education and enforcement of alcohol-related laws.

I thank you for your time and attention.

DR. ELLINGSTAD: Thank you, Mr. George.

Our next panelist is Dr. Jon May with the National Association of Boards of Pharmacy in Gaithersburg, Maryland.

DR. MAY: Thank you.

I am a consultant to the National Association of Boards of Pharmacy, and I bring you greetings from them. The Executive Director, as I speak, is in Monterey, California, attending the NABP Executive Officer's Conference.

In the parlance of the recently-completed World Series, I am a pinch-hitter. I live in Gaithersburg, Maryland. I retired from the U.S. Public Health Service in 1992, having spent 10 years with the Food and Drug Administration.

When I talked to Dr. Garber after I was asked by NABP if I was available for this meeting, he told me that we would have about a five-minute time for a statement and that most of our input would come from the questions from the panel and/or the audience.

So, I have a statement that has been prepared by NABP. If I read it real slow, it'll reach five minutes. If I read it at my normal talking pace, it will probably take three minutes. So, I will present the statement from NABP, and then we will field questions, although we feel like we're being targeted up here with only two. I came in an hour ago, and there were five people sitting at this table. So, I'm beginning to worry a little bit.

Anyway, what we responded to was the question presented by NTSB, and it goes, what types of local requirements serve to restrict transportation operators from operating vehicles under the influence of potentially impairing medications, and how are/can these requirements be enforced?

From the State Board of Pharmacy perspective, the scope of direct authority over transportation operators is extremely limited. Pharmacists who fall under the direct authority of the state boards of pharmacy are required to affix warning labels to medication containers dispensed to patients if the medication could affect a person's ability to operate a motor vehicle or heavy machinery.

The medications causing the side effects are usually agents which cause drowsiness by impacting the central nervous system. The labeling requirement, although not specifically stated in the State Practice Acts and regulations, is based upon good standards of practice that any pharmacist would use in order to ensure that the patient is safe from harm.

State pharmacy boards ensure that these practices are occurring through random inspections and review of documentation for the specific prescriptions. The only other means for regulating and responding to such activities would occur if a patient was injured and formally complained to the state board of pharmacy that they were not adequately warned about the side effects of the medication. In this instance, the pharmacist, not the operator, would fall under the jurisdiction of the state board.

Although there is a clear indication to the pharmacist because of his or her knowledge of medications of which medications could have sedating effects, there is no federal mandate from the FDA designating these medications and requiring a specific warning label.

Even if this requirement was in effect, NABP is not certain that such a federal mandate would help resolve the problem identified by the NTSB. Although it would place a specific legal mandate on pharmacists to affix the appropriate label, the state boards of pharmacy would not have any authority over operators who actually are prescribed and take the medications.

The responsibility for pharmacists to make this warning known to patients is inherently present in good practice standards and could result in disciplinary action against the license of the pharmacist if not followed.

NABP is willing to work with the NTSB and FDA to resolve the concerns identified.

DR. ELLINGSTAD: Thank you, Dr. May.

We'll go for questioning to the Technical Panel. Who wishes to go first? Dr. Garber?

Questions from Technical Panel/Parties and Discussion

DR. GARBER: And Dr. May, since you spoke last, I'll question you first, if you don't mind, and if there are issues that I touch on, Mr. George, that will -- that have legal implications, I would hope that you would jump in and respond to those as well.

In Australia, the pharmacy associations there sort of banded together and got a standardized warning label that they use for a certain list of medications. It's a red warning triangle that sits on the same sort of stickers that are commonly applied in this country.

So, what I'd like to ask is, do -- is there any opportunity for pharmacists in this country to do a similar sort of thing, and to what extent do you feel that that might be effective on a voluntary basis?

DR. MAY: Well, I read that in the report, and I'll have to ask you a question. I haven't seen it. Is the red triangle simply that?

DR. GARBER: Exactly.

DR. MAY: Does it have words?

DR. GARBER: It's just a warning.

DR. MAY: Nothing?

DR. GARBER: It's a red warning triangle, which is actually a very common symbol in Australia for danger. It's a road signal that's fairly commonly recognized as meaning dangerous conditions ahead.

DR. MAY: Okay. Well, it appears to NABP that there are several problems with that. One, that does not mean that in the United States. In Pennsylvania, on the back of an Amish buggy, it means go slow.

I don't think anybody here would recognize it. There would have to be a tremendous educational program to tell people that that really has some significance. What they put on now, as you know, is a little label on the back side of a prescription label on a bottle that says caution or warning, this drug may be sedating, may cause -- do not operate machinery, drive a car, etc. It is a warning.

It's a well-known fact that a lot of people who get prescriptions in this country really don't understand the prescription label itself, let alone some of the warnings that are attached to it, and sometimes there are more than one warning attached to a prescription. There may be two or three.

When they turn that over and start reading them, multiple warnings tend to have a lessening impact on the observer. They see all this, and they start wondering what it really means.

The one about sedation, and we've all taken sedating antihistamines by prescription or over-the-counter, and you were aware of these warnings, and you read them, and they tend to really not excite you too much because I've taken them, and I've not felt that I've experienced the effects.

I guess what I'm saying is to put the red triangle on or something similar to that, we're having a hard time understanding how that might improve the label now that is in English. You can read it, and you have, I think, a better understanding of it, unless again you can educate the consumers that this now has a new meaning, like the radiation symbol in this country. Everybody understands what that means, and if they see it on any product, it catches their attention because they've been educated to it.

When I read this again in the docket, I had some problem with the triangle concept, something without words, because I'm not sure again that you're going to be able to do this in the minds of the consumer, that they see this little red triangle or yellow circle or whatever you make it on a prescription, that it's going to have the same impact as a label where, if they read it and understand English at a certain level, they will at least comprehend what that little thing means.

So, I guess I would throw it back and say unless you're willing to undertake a really massive education program when you undertake something like this, I think you probably will have great difficulty with it at first.

So, it's possible that it could work, but it would have to be proven that it's any more effective in a way than what's put on there now. Unless you mandate that a certain level developed by FDA, which we'd probably agree with, the agency, along with its consultants and the public, looking at a prototype product would agree that that's better than what's put on there now by pharmacists, we would be happy to do that, if that can be improved, if you can get the attention of the public who reads those labels, but that system in use in Sweden and Australia may work there, although I haven't seen any data here that it really works. It just says it's being implemented.

So, we're agreeable to something that improves the present system, but it's a hypothetical to know whether that can be made to work in a short period of time or even in a longer period of time.

DR. GARBER: So, do I understand correctly that the position would be that if a warning label were developed that could be shown to be more effective than current warning labels, that your organization would find that to be an advantage over the current system and would voluntarily use such a system?

DR. MAY: I would say that's true, using the caveat that I used, that it is a better system and would have a better impact on the consumer or even on anyone taking a product. That's right.

DR. GARBER: Okay. You mentioned that the requirement of affixed labels is really a best practices requirement; that is to say, that it's done because it is a standard of practice in the pharmacist community.

So, do I understand correctly then that there is no state law, federal law, regulatory guidance that would suggest that you must put any warning label on a prescription medication?

DR. MAY: Oh, no. There are some warning labels that are required to be put on the medication, but what you would hope for, what we would hope for would be if you could come up with a very effective warning, which would help solve this problem, if that could be made a federal standard, it would make it a whole lot easier for the 50 states to adopt as opposed to state regulations which may vary all over the place. One state may make it a regulation, another one may make it simply a good practice.

Pharmacists put a lot of these labels on because it is good practice. Whether or not there are state laws, I cannot tell you in all states. I'm here to talk about the overall general concept of trying to improve the labeling put on there now.

It was mentioned in here by NTSB that something that was -- I think I read it, something that was in a mandate would work a lot better, but again you have to prove that there should be a federal or state requirement for it as opposed to standard practices.

DR. GARBER: And actually, my next question goes to Mr. George in regard to that same issue.

How many states actually have laws that specifically prohibit use of impairing medications? Do you have any feel for whether most or many states have such laws?

MR. GEORGE: I can tell you what we have in Delaware. My thought is that probably every state has a similar DUI statute that prohibits not only the driving while under the influence of alcohol but of an impairing drug as well. So, I would have to say that my feeling is that probably every state has some statute.

DR. GARBER: You mentioned some of the difficulties inherent in trying to prosecute a case involving medication versus one involving alcohol or, I assume, illicit substances as well.

Does -- do you believe that there are -- that there is less activity on the part of law enforcement in trying to determine whether people may be impaired by drugs or perhaps even if that determination is made, given the very difficult hurdles that may need to be cleared to prosecute such a case, that such cases are not -- even when found, may not necessarily be prosecuted or evaluated completely?

MR. GEORGE: Well, I think the problem with an impaired driver, impaired by medication, is that the impairment has to be such that they're falling down drunk, like an alcohol-type case.

Police are limited in what they can do, based obviously on the Constitution. Before they can take blood samples or urine samples or an intoxilyzer, there has to be probable cause. So, the person that they stop has to exhibit some type of outward signs of intoxication. That's the first hurdle.

If they are impaired to the point where they can't do field tests, the standardized field tests, then the next step would be the officer is probably going to assume that they're impaired by alcohol. He's going to probably take them back to the troop and give them an intoxilyzer.

The problem there is he's going to get a 00 reading, and he doesn't know what to do then. It looks like the person's drunk. They're showing no reading, and they're sort of stymied at that point, and that's the problem with the training at this level in the state of Delaware.

DR. GARBER: So, if we were to look at a database, a hypothetical database of non-fatally-injured drivers or drivers who were potentially at fault in a traffic accident, would it be safe to say that we would probably under-represent the risks associated with the medications simply because it's so difficult to detect, and if one detected, difficult to -- or suspected, difficult to prove?

MR. GEORGE: Absolutely. I would agree with that.

DR. GARBER: Okay. I may have a couple more questions, but that's all I've got for now.

DR. ANDREASON: This is a question for Mr. George, but Dr. May, if you happen to know the answer to this, too.

What are the -- do you have a list of drugs that are considered impairing or is that statute fairly open to interpretation?

MR. GEORGE: When it comes to -- the statute reads it prohibits the driving of a vehicle while under the influence of any drug or under the influence of a combination of alcohol and any drug, and we obviously take that to mean both legal and illegal. So, that's exactly how our statute reads. So, it would encompass legally-prescribed drugs, if it impairs you.

DR. ANDREASON: Any drug?

MR. GEORGE: Any drug.

DR. TEMPLE: Is under the influence described further?

MR. GEORGE: It is defined, but I can't specifically say how it's defined right now.

DR. TEMPLE: Is there something that implies, though, that your performance is impaired?

MR. GEORGE: Yes.

DR. TEMPLE: Okay. But it doesn't give any hint as to what kinds of drugs might be there? You're on your own?

MR. GEORGE: You're on your own.

DR. ANDREASON: So, if someone had a blood alcohol level that was, say, below .02, and they were taking a non-steroidal anti-inflammatory drug, that would be considered in combination with alcohol?

MR. GEORGE: Well, our statute has -- sets out five different definitions of being impaired. It speaks specifically to alcohol, and in our state, a reading of .01 or above is considered under the influence. A reading from .05 to .09 is presumptive evidence that you're under the influence, and a reading of .05 and under is not considered under the influence.

So, in your example, a reading of .02 and an indication that there was some other drug involved, that case, if we were to take it to trial, we would have to have evidence of beginning first with the field tests that are performed by the officer, and I'm assuming everybody knows what I mean when I talk about standardized field tests. They're the walk and turn test, the picking up the keys, the counting, the alphabet, reciting the alphabet. In some instances, tests involving HGN, and those -- the performance on those tests would have to be so poor because that would in essence be all the evidence to make or break this particular DUI case because obviously when you take that individual back to do an intoxilyzer reading, it's going to come back with an .02.

So, to prove that case, you're going to have to have pretty poor performance on the field tests to be able to obtain a conviction. Now, whether steroid drugs would cause a person to perform that poorly, I can't speak to that.

DR. ANDREASON: What kind of field -- now, you described a field test. How do those correlate to, say, driving performance? I assume they've already been pulled over because of some erratic driving. Why do the field tests need to be repeated?

MR. GEORGE: Because an officer can't take someone into custody without probable cause. That's one of the fundamentals of our Constitution. The officer begins his case by noticing the erratic driving. That gives him the reasonable suspicion to stop the driver and then begin the process of developing probable cause, what we call probable cause. The erratic driving is the first thing.

The next thing that a trained officer will do is he'll go up to the car, and he will look into it, you know, see if he gets the odor of alcohol. There's initial signs of impairment, such as speech, looking at their eyes to see if they're bloodshot, and some of these signs will be the same if someone's impaired by medication versus alcohol.

Obviously if they're impaired by medication, you're not going to get the smell of alcohol. He's going to ask for their driver's license, registration, and he's going to look to see if they have difficulty in the pulling out of the glove compartment or out of their wallet, if they fumble with them, if they give them their Acme card instead of their driver's license. Those are the first things that he's noticing.

At that point, as he continues to develop his probable cause, he's going to ask the driver to get out of the car. Again, he's going to note whether they had difficulty in getting out of the car, whether they had to lean on the car, whether they stumble, and again, he's developing probable cause. He doesn't have it yet.

He'll then give a series of field tests and note the performance. Now, I'm not an expert in field tests, but I know that NHTSA has done a number of studies, and I can't tell you the percentages off the top of my head, but I know that the studies have shown that if you fail certain -- and NHTSA, I think, recommends three standardized field tests, and if you fail these field tests, there's a 70-percent likelihood that you are probably under the influence of alcohol.

Combine that with an HGN test, which not all officers are trained to do, your percentage goes even higher, that the person is most likely under the influence. At that point, the officer has developed his probable cause that he needs to either give an intoxilyzer or to take blood. So, it's a step-by-step process to that point of actually being able to give the field tests. You just can't stop someone, anyone you want and say, hey, I'd like you to do some field tests for me. It's a step-by-step process.

DR. TEMPLE: Once that test establishes probable cause, then they can make somebody exhale into an analytic procedure?

MR. GEORGE: At that point, he has established probable cause. He can arrest the individual and either take them back to the troop and give them the intoxilyzer or, in his discretion in our state, take the blood test.

DR. TEMPLE: Okay. I was going to ask about saliva tests, but he can get a blood test in Delaware?

MR. GEORGE: Well, our statute specifically requires a blood test. At one time, it provided for a urine test, but that was never done, and it was really meaningless.

DR. ANDREASON: Field testing does seem to be weighted to detect alcohol, especially with horizontal gaze and walking a straight line, which are cerebellar functions.

If someone was impaired, say, by other drugs that didn't affect cerebellar functions, what would the officer be able to do? Must they fail these tests in order to be tested or to obtain a blood test?

MR. GEORGE: Keep in mind, I'm not a chemist, I'm a practicing prosecutor.

DR. ANDREASON: Right.

MR. GEORGE: However, I'm not sure I totally agree with you. I do know about the DRE program. We've -- I've -- we initially had a conference in Delaware at one point where we brought out Sgt. Tom Paige, who helped to develop it in L.A., and I know that with a drug recognition expert, who is a trained police officer, who is ultimately based on his training able to detect or determine seven broad categories of possible drug impairment, they begin with the standardized field tests.

So, the standardized field tests not only are geared towards alcohol but are geared for drugs as well. The HGN test is geared not only for alcohol but for drug impairment as well. The problem is, that's the extent of the training for most police officers. The training necessary to later determine whether it's a drug impairment is much more extensive, and in Delaware, we don't have such a program. That's where the problem comes with detection of drug impairment.

DR. TEMPLE: Do you have programs for obtaining blood samples from people killed in accidents and other people in the car? Still thinking epidemiologically from the last panel, but I just wondered if that was a resource.

MR. GEORGE: Well, anyone who's killed in a motor vehicle accident is taken to the state medical examiner's office. Keep in mind, Delaware being so small, everything's sort of run at the state level. We have no county district attorneys, no county MEs, and so, everyone in Delaware who would be killed in an accident would be taken to the ME and an autopsy performed and blood tests. So, yes, absolutely.

DR. TEMPLE: Do you know, have data ever been looked at to compare blood levels of various substances of interest in drivers and passengers or anything like that been published?

MR. GEORGE: I know that our Safety Council does publish yearly the statistics involving fatalities, and I know that they keep track if the driver of the automobile has -- was intoxicated. I do know that. Whether they look for other drug impairment, I don't know.

MR. KOTOWSKI: In the case where an enforcement -- where a motorist is stopped and is pulled over at the roadside and has been subjected to these battery of tests and obviously there's some difficulty, when it comes time when we have a blood test that is drawn, do we have to be specific about a particular type of drug or is there just a general screen or a general scan that would be taken of that particular drug sample?

MR. GEORGE: Again that's a little bit out of my area of expertise, but based on some experience I've had in that, I know they always check for alcohol. I know that they always check for certain illegal substances, PCPs, cocaine, and several others.

I don't believe, unless they are specifically advised, that they would look for an illegally-medicated type of drug, unless it's some type of barbiturate, illegal barbiturate.

MR. KOTOWSKI: If you could, could you walk us through your procedure as a prosecutor, some of the difficulties you would face, that if you had a motorist that was stopped, that failed all these tests, had a blood sample that was taken, came back positive for some type of a prescription drug, that when you checked the PDR, it says that it is a sedative-type medication? You have a reading that there was a certain percentage or a certain level of this particular drug in that person's blood system, the big AC level is about .07, what would you have to do in order to provide for a successful prosecution about the establishment of the effects of that particular drug?

MR. GEORGE: That case may be a little easier to speak to because we have an .07 alcohol and that's within the range where the trier of fact, whether it be a judge or a jury, could find a person under the influence of alcohol or a combination of alcohol and drugs.

Again, any time that you have a finding where there's some type of drug involved, and a finding where the blood alcohol is under 10, the prosecutor has to really rely on the performance on the field tests to prove that the person was impaired.

Without a very poor showing on the field test, you're going to have difficulty in obtaining a conviction. It is possible, and I've done this in several cases, depending on the blood reading of the drug that's detected, that we would bring in one of our forensic pathologists, one of our assistant medical examiners, to speak to that particular drug.

I certainly know in instances where we find illegal substances, like cocaine or PCP, the medical examiners are usually quite willing to come in and talk about the effects of that particular drug and whether it would impair you or not, but again the issue for the trier of fact is, was this person impaired?

They're going to be looking. They're going to focus mainly on the field tests, and unless we have some kind of expert testimony regarding the effects of that, that finding of the drug may or may not be that important to us.

MR. KOTOWSKI: So, in most cases then, for any particular type of drug, then it would almost necessitate the testimony of an expert witness?

MR. GEORGE: It would always require the testimony -- well, no, I don't want to say that. Again, if the field tests are just so poor, and again I'm going to kind of refer back to an alcohol-type case where the person looks like -- who is literally falling down drunk, then I'm not going to need an expert.

But if the field tests were so-so, then without an expert, there's no case.

MR. KOTOWSKI: And the reference that you made to the DREs, the drug recognition experts, do you know how long that training program lasts to train an officer as a DRE officer?

MR. GEORGE: I don't, but I know that after the training, I think that they require at least 90 hours of field experience with other DREs and working at hospitals before they actually go out and start working on the streets.

Part of the training for a DRE involves taking vital signs, measuring the pupil, and I think that that training, the 90 hours, is done in hospital emergency rooms.

MR. KOTOWSKI: And do you have any idea of how long it would take for a drug recognition expert to make a stop, identify a person that's been under the influence of some type of drug and be tested and arrested as compared to a person that's under the influence of alcohol?

MR. GEORGE: Well, it's usually the DRE isn't making the stop. The stop is made by another police officer, and the DRE is called in afterwards to basically do the field tests and conduct this examination. As to how long it takes, I don't know.

DR. ANDREASON: Dr. May, I had a question about how do you determine which drugs you put a label on or a warning label on for supervision.

For example, is it from product labeling or is there some other source of information that you use to place the label on?

DR. MAY: It would be my understanding that the pharmacist, from his knowledge of the drug being dispensed, there is -- when he opens up the bottle of pills, if there's nothing on the federal label that says you must put a sticker on this, but if he's dealing with antihistamines, dealing with drugs that he knows to be sedating, whether it's the benzodiazepines or antihistamines or whatever, from personal knowledge, experience and training, he knows that label goes on there to warn the person that this may cause problems if they operate an automobile or heavy machinery.

I'm not aware that there's any -- I haven't worked in a pharmacy for many years, but there was never a federal requirement that that label had to go on there. When the state board people inspect and go back and look at the prescriptions to see if they're adhering to this, they'll look for any prescription that they know to be sedating, and these don't carry any particular mark on the computer file or in a hard copy file as narcotics would.

They're looking for the names of drugs and knowing what they cause, and they're looking to see if in fact a label was put on there by the pharmacist. They'll watch pharmacists fill prescriptions, but that's how the system operates. It's a professional knowledge. There is no chart they look at that says you have to put this on for this class of drugs -- for class of drugs but not specific drugs.

DR. ANDREASON: Another question is, do you have any idea how much sedation is necessary before a label goes on? For example, I've received prescriptions for Naprosyn that have a warning label that it could be sedating.

DR. MAY: To my knowledge, that information does not exist. Pharmacists do not use that. You're getting Benadryl or you're getting another antihistamine, you're taking one three times a day or you're taking two every four hours, when the dose is much higher in one case over a 24-hour period, the same label goes on the product, warning, based on the drug itself, because a lot of people will get a prescription, especially over-the-counter drugs, and will overdose. They will take more than the indication.

It says one three times a day, and it's an antibiotic, they may take two. They may take more than the indicated. So, you put the label on based on the pharmacology of the drug. If it has the property, propensity to be a sedating drug, you put the warning on it, regardless of the blood levels the patient may experience from taking it for different levels of the drug.

DR. ANDREASON: Thank you.

DR. ELLINGSTAD: Anything else from our Tech Panel?

(No response)

DR. ELLINGSTAD: Okay. We'll go to the parties, and let's start with the Advocacy Group this time.

MS. TARNEY: This is for Jon May. Are you of an opinion that pharmaceutical care these days means that the pharmacist can be held accountable for reaching or for resolving patient needs related to the medication taken as directed?

If so, would you think it's possible in the present situation or the near future that a pharmacist advises the prescriber and the patient to use the least impairing drug in case the first time prescription for a hypnotic, let's say, shows a severely impairing drug?

In other words, can the -- do you see in the future where the pharmacist could take the role of an advisor to the physician as well as to the patient?

DR. MAY: I'm glad you raised that. Yes, I firmly believe in that. NABP believes in that, and all of the pharmacy professional associations I know believe in that. The paradigm has shifted where pharmacy is no longer just filling prescriptions, counting them, licking them, stamping them, pouring. That's being done by technicians hopefully, and the pharmacist is counseling the patient. The pharmacist is specifically making sure the patient understands the drug they're getting, what did the doctor tell them about it. If that's inadequate, reinforcing what they need to know.

The Keystone Group met several years ago and developed a mandated written information system for people receiving prescriptions under a federal statute. It was a rider to a federal bill, and one of the things missing in that, in my opinion, is, although they give very good printed information today when you get a new prescription, you get an insert that tells you all about that drug. There's a tremendous amount of information in there in the case of sedating antihistamines, in the case of benzodiazepines, etc. It warns about this particular drug.

But unfortunately, what a lot of pharmacists are doing is putting that little information pamphlet on the bag with the prescription, and they slide a piece of paper in front of you, and when you look at it, it says do you wish to be counseled? That's inadequate in my opinion. That's inadequate in NABP's opinion, because too many people say, oh, no, I'm in a hurry, I don't need it. They X it out, and they go, and unless they open up that pamphlet and read the information, they really don't know much more about the drug than what was provided to them.

The role of the pharmacist, in my opinion, and it will happen over a period of years, is he will take every patient, and he will go over that drug with them, and he will not only show them the pamphlet, but he will reinforce parts of it.

One of the beauties if you go into a system where you're worried about these drugs that can cause these problems with pilots and with operators of heavy machinery as well as the consumer is they have to be made aware of the very thing you're talking about. These drugs have potential dangers to them, and you can reinforce that best when that person gets that prescription at the pharmacy, and the pharmacist tells them that. Oh, by the way, do you see this little label on here? See this little red triangle or whatever? This means that this product has the potential for.

You focus it in their minds, so when they leave, then they read the information pamphlet, that's going to stay with them. They're going to react to that. They're going to be aware of that. They may continue to ignore it, but you've made your point of reinforcing it in their minds.

Today, that does not exist adequately enough, but it is changing because the role of the pharmacist is changing, working more closely with physicians in delivering health care, not just delivering a prescription, and making sure that the ultimate end result occurs when they take that prescription. They're taking it right. They're taking it in the right amount of time, and they know what they're taking.

So, that's what pharmacy is coming to, and that can fit in well with this type of approach where you're changing -- hoping to change a labeling system and an awareness on the part of the public that these drugs are not just innocuous things you're taking, and they get that reinforced in their minds in some respects by getting no information from either the doctor or the pharmacist in some cases. They just get this prescription that says take one three times a day, and they start taking it.

No awareness of what this is supposed to do or the side effects that can result from it, unless they get counseling, unless they read this information they get. So, that's a long way of saying yes, I agree with you, and that's what pharmacy is changing to, and if that was done today in this instance, you would not see some of these accidents, I'm sure, because the patients would have been told right up front beware, this drug can really produce sedating effects and don't do some of these things, along with an education program for people like pilots, etc., that's the other aspect of this.

It kind of intrigued me when I read it. You can do all the labeling you want in the world, but unless you educate the segment of the population that has responsibility for flying $20 million airplanes with 300 people in them that they shouldn't take certain drugs or if they are, they should advise their surgeons that operate over them that they're doing this and get permission to do it, get some awareness of it, we're going to continue to have problems, and you do focus on education in here, but that's a big aspect of it, also.

I'm talking about the pharmacists educating people when they pick up prescriptions as well as labeling. Labeling can only go a certain way. The rest of it is education and making people aware of what they're supposed to do and the danger of these drugs they're taking and some of the side effects.

MS. TARNEY: Do you see the role of the pharmacist also to question a physician if the pharmacist is seeing something that is not safe?

DR. MAY: Absolutely. When I graduated from pharmacy school in 1959, I was -- we were all afraid to call a doctor. We were afraid of what he'd say. What the hell are you calling me for? Just fill the prescription, and I ran into people when I was with the government and at NIH. NIH physicians basically told me that. You fill the prescription, I wrote it, don't question me.

Today, that's totally changed. Pharmacists are calling physicians and saying, in hopefully a tactful way, doctor, I've talked to the patient, and this drug, I think this drug is either contraindicated or are you aware that the patient is already taking another drug which they probably weren't aware of. They're interacting with the physicians because the bottom line is the outcome of the case, the patient getting better taking the drug.

The only way to do that is if pharmacists start becoming more interactive, working with nurses and physicians, to make sure that the system really benefits the patient, not the physician, not the pharmacist. They're secondary to the patient and that's another whole shift in this thing coming.

I can go on for hours about these protocols being developed between physicians and pharmacists today, where the pharmacist actually delivers care. They do -- they take blood. They determine Dilantin levels. They determine levels of drugs, working with physicians under protocol, because the physician then can spend more of his time doing the diagnosis, doing the prescribing but not having to do some of that other information. They're counseling patients who have asthma, so that they don't go back to the doctor and say Doc, this medicine isn't working, when you find out they're not using the inhaler right. They learn to do that from the pharmacist.

A system that works hand-in-hand is going to result in better care in this country. So, that's changing rapidly today, I'm happy to say. It's moving forward in every state in the Union.

DR. ELLINGSTAD: Okay. Let's go to the Government. Mr. Clarke?

MR. CLARKE: Mr. George, you indicated that the procedure seems to be field tests and then an intoxilyzer and then blood possibly or can you go from positive results in a field test straight to blood and skip over the intoxilyzer?

MR. GEORGE: That's at the discretion of the police officer. Another one of the possible tests is what we call a PBT, a portable breath test. That gives an initial unscientific, I guess, reading of the blood, and if that were to come back 00, if the person has been done so poorly on the field test, then the officer, in his discretion, can have a blood sample taken.

In fatal cases, we usually take blood because we're -- we don't do an intoxilyzer. We take -- once we've developed a probable cause, we'll have blood taken because we're always suspicious of whether there's alcohol, drugs or a combination of both involved.

MR. CLARKE: You mentioned that there was some number of drugs that you test for, in addition to alcohol, and I presume those were all illegal drugs.

If you get a situation in which you've gotten poor field test results but zero readings, say, on an intoxilyzer and this other test, and you get some kind of positive readings on any of these illegal drugs, what success do you have then in prosecuting those cases?

MR. GEORGE: Well, again, it's really going to depend on the field tests because I'm not sure it makes much difference. Obviously with an illegal drug, it's more prejudicial when you present it to a jury, but ultimately again, the issue is one of impairment, being under the influence.

When we get the blood test back, if it's a legal drug or an illegal drug, I'm still going to have to prove that the person was impaired by that particular drug. I suppose you can take small amounts of cocaine and still drive a car and not be impaired, just like there are a number of legal drugs that you can take and not be impaired.

The problem that we have is when we get that blood test back, and I take it to one of my experts, and I say, look, at this reading and tell me what it means, and if it's a legal drug, he's probably going to tell me, well, that's a therapeutic dose. That's very nice. What does that mean? There was a therapeutic dose in this person's blood. Does that mean he was driving under the influence? I don't know.

MR. CLARKE: So, if you get low levels of any of these drugs, but you've still got poor field test results, you don't have the basis for going forward with the prosecution?

MR. GEORGE: Without the poor field tests, we won't have the basis. Again, you know, the therapeutic dose, the fact that it's in the blood may be relevant, may not be, but we're really going to have to rely on the field tests to be able to prove that.

MR. CLARKE: Is that the most convincing aspect of a prosecution or are these quantitative measures more compelling?

MR. GEORGE: No. The field tests are absolutely the most compelling part. Really, as far as drugs are concerned, and unless the dose is just so high, the quantitative effects really can have a lot of meaning to the prosecution.

MR. CLARKE: Are there any cost considerations associated with making decisions to draw blood as opposed to just relying on the intoxilyzer results? If you were routinely doing this on large numbers, how would -- what would that do to your budget?

MR. GEORGE: Well, again, the decision is at the discretion of the police officer, and then I think -- and I'm not a police officer, but I would think that some of the factors that go in his decision whether to take blood or intoxilyzer is that the intoxilyzer is easier. He has to go back to the troop and do it, takes about 30 minutes all together. He's at the troop. He can write his reports versus having to take a blood test requires him going to the emergency room --

MR. CLARKE: Right. But we're talking about situations here where presumably the intoxilyzer tests are negative. In other words, just -- we're looking at just effects of prescription or OTCs, without confounding effects of alcohol.

MR. GEORGE: Well, if he's already given an intoxilyzer, then he's not going to take blood, too. He makes that decision at the time.

MR. CLARKE: So, to get a zero reading on the intoxilyzer, you can take blood?

MR. GEORGE: Probably not.

MR. CLARKE: Even though he had poor field tests?

MR. GEORGE: He's going to probably assume it was alcohol. He made the decision before he leaves the scene and of whether he's going to take the blood or intoxilyzer, and once he makes the decision, he's not going to do both.

MR. CLARKE: But I guess my question is, if he does poorly on the field tests, giving the officer an indication of probable cause, then goes back to the police station, I presume that's where they go, and then gives them an intoxilyzer test and gets zero, then what happens?

MR. GEORGE: He's unlikely to then -- on just a regular DUI, it's very unlikely that he's then going to take him to a hospital and do blood work.

MR. CLARKE: So, I guess what I'm trying -- what has to be present for the person, for the officer to decide to draw blood? A pretty bad field test and the intoxilyzer or just one or the other?

MR. GEORGE: Well, maybe I haven't made myself clear. The officer has some -- can do either. He can either give an intoxilyzer or he can decide to have blood taken. In fatal cases, we make the decision right at the scene that we're going to have blood taken. We're not even going to bother with the intoxilyzer.

Once the officer takes that person into custody, arrests them, he makes the decision, am I going to take him to the emergency room and take blood or am I going to take him down to the troop and give him the intoxilyzer? He makes that decision at the scene. He doesn't know what the reading's going to be, but he's making the decision of these two options. I'm going to do one of them.

Once he makes that option, he takes them back to the troop. He gives them the intoxilyzer. He comes back 00. In a DUI case, it is very unlikely that he then is going to turn around and take the person back to the emergency room and take blood.

MR. CLARKE: I guess also, I'm looking at it from your point of view as a prosecutor. You've got this information in hand, say poor field test results, zero -- he just went right to a blood test because that's it, and you've got zero blood alcohol but maybe trace levels of some of these five illegal drugs, one or more of them say, let's say one that you're talking about. What do you do as a prosecutor at this point?

MR. GEORGE: I'm going to talk to my experts and try to determine if the therapeutic level -- what the therapeutic level of that particular drug, what it means. Will they testify that that level is impairing?

But even with their testimony that that is an impairing level, I'm going to still need poor field tests to be able to convict that person of driving under the influence. The level itself, unless it's just incredibly high, is not going to be sufficient to sustain my burden, which is to prove someone guilty beyond a reasonable doubt.

MR. CLARKE: Thank you.

DR. ELLINGSTAD: Let's go to the Professional Group.

MR. GELULA: Thank you. I have two questions, the first for Mr. George.

Today, we've mostly been focused on sedating medications, drug interactions and combination of sedating medications with alcohol, but a number of studies have also shown that total hours of wakefulness or sleep deprivation can cause impairment as great or equal to alcohol intoxication.

I'm wondering if, in your experience, there's been any evaluation or roadside tests whether there's any effort to judge whether there's an additive effect of sleep deprivation or time of day, the circadian effect, and such. Would those factors come in?

For instance, if it's been adjudged that the person has been up for the past 24 hours, is that a factor that you use in trial?

MR. GEORGE: Absolutely, and I have done a number of commercial vehicle cases. In particular, I finished one up about a year and a half ago that you may be familiar with. A truck driver coming down a major roadway in Delaware came up on a red light.

All the cars were stopped, and he plowed into this row of cars. The van that he initially struck was totally demolished, burst into flames, people burned to death, and we ultimately were able to show that over a -- he had a GPS system in his truck, and we were able to show that over approximately 55-57 hours, that he had been on the road for close to -- all but for about 13 hours, just way over his hours, and that obviously was a factor in whether we were going to charge him.

Keep in mind that not every fatal motor vehicle accident involves a criminal prosecution. In Delaware, we need to rise to the level of what we call "criminal negligence", which is a much higher standard than just simple negligence.

People who negligently kill other people are not prosecuted criminally. They may be sued, but they are not prosecuted criminally. So, we had to make a case of criminal negligence. Obviously part of that case was the fact that he didn't see all these cars stopped at a red light. He plowed into them at 60 miles an hour, but the other major factor in that particular case was the number of hours that he had been up, and I think that played a very important factor in our successfully convicting that driver.

MR. GELULA: Thank you.

And Dr. May, I'm curious if in your experience or if there's evidence to suggest that patients might be substituting an over-the-counter drug, if they make that choice, instead of going for the filling of a prescription or, for instance, a hypnotic because they might believe that the OTC brand is safer. Do patients make that kind of decision?

DR. MAY: I missed the last -- your last comment, the last words you used.

MR. GELULA: They might believe that the OTC brand is safer than the prescription drug. Do they make a substitution?

DR. MAY: I really can't comment on other than drugs that exist for both prescription and over-the-counter. There are people who will buy a Motrin prescription, a high-dose prescription, low-dose over-the-counter, people buy low-dose over the counter because they don't go to a physician to get a prescription. I'm sure that goes on.

Other -- going to other drugs, I really can't comment on that.

MR. GELULA: Thank you.

DR. ELLINGSTAD: Thank you.

The Pharmaceutical Industry? Would you make sure your button is up?

MR. LISTER: I'm Steve Lister. I'm with the Consumer Healthcare Products Association.

DR. ELLINGSTAD: Could you say your name slowly, so we can get it?

MR. LISTER: Sure. Steve Lister.

DR. ELLINGSTAD: Lister?

MR. LISTER: Lister, like mister. I'm with the Consumer Healthcare Products Association, and I don't think I have any questions for the panel.

DR. ELLINGSTAD: Thank you.

The Union Group?

CAPTAIN POPIEL: No questions.

DR. ELLINGSTAD: Thank you.

And finally, the Transportation Industry Group?

DR. FAULKNER: Yes, I have a question for Dr. May. Habla Espanole? Sprechen sie Deutsche?

The reason I ask is, you know, we're in an international business with airlines, trucking, things like that. I certainly admire and support pharmacists working and explaining things, but we're going to hit language barriers, and one thing I've encountered or it's been encountered here is warning labels will often have pictures, but those vary from someone sleeping in a bed to drowsy eyes to the like.

Has there been any move or is your organization advocating for perhaps more picture-type warnings for perhaps the illiterate or people from out of country for warnings?

DR. MAY: Yes. NABP is certainly in favor of these pictograms that we put on prescriptions or on over-the-counter drugs particularly to let people know.

Giant Pharmacies in this area have been very active in that for years, putting -- getting the suppliers of their products to put certain pictograms on there.

We're fully aware of the Spanish problem or the language problems, rather, and communities where there are major populations of Hispanic people, etc., or in California, where there are Asiatics or Asians, there are pharmacies that label prescriptions in that language and put warnings on in Spanish.

If someone speaks Spanish predominantly, you're not going to hand them a product that's labeled necessarily in English. So, there's a lot of that going on to help the patient again get the medication, so they can get the ultimate outcome from it. But a lot more needs to be done.

DR. ELLINGSTAD: Okay. Thank you.

And we have some questions from the audience from Dr. Galson.

DR. GALSON: Yes. We've got one statement and really two questions. I think I'll do the questions first, and if we have time for the statement, I can read that. This is for Dr. Jon May.

Would mandating the pharmacist to educate the patient in regards to certain medications causing sedation and warning labels be more effective than the current practice?

DR. MAY: I heard it, but you'll have to say that again.

DR. GALSON: Would mandatory requirement on the pharmacist that they counsel patients be more effective than the current system, which is voluntary?

DR. MAY: Well, for Medicare patients, the system is mandatory, but what happens is when the law was passed and then it was implemented, there were some segments of the industry that wanted to be sure, this is my perspective on it, wanted to be sure that this was not a very harsh implementation of the law requiring that if the patient was standing there, that I had to be the pharmacist and do the counseling.

So, it was made so that some of the counseling, a technician could actually ask the patient, do you want to be counseled, and then if they said yes, they would call the pharmacist out, but you can get around that by the way you ask questions obviously. You don't want to be counseled by the pharmacist, do you? Well, if you ask it that way, why would I want to be counseled by the pharmacist for?

When I go into my drugstore, as I say, I won't name them, I get a piece of paper laid in front of me. Even if they didn't know me, the very first time, instead of the pharmacist coming out and saying what do you know about the medication you're taking, and I would have said I don't know anything about it, and he would have counseled me.

They slap a piece of paper, and I'm a pharmacist. I've gone through this. I play games with them sometimes. I got tired of playing games when I used to tell them I'm a pharmacist, what should I know about the drug I'm taking? One of them looked me in the eyeball and said, "What do you want to know about the drug you're taking?" This guy ought to be selling cars, not a pharmacist.

If you do it very proactively, you do get that type of counseling, but it is, to answer the question, it is a requirement today that Medicare patients get this.

What the states have done is they said you can't just counsel Medicare patients, Medicaid patients. So, we're going to counsel all patients, and they do indeed do that, but they do it but with varying degrees of success. Some stores are very proactive and the pharmacist will go out and go through the very litany of things I talked about, using basically a system developed by the U.S. Public Health Service, Indian Health Service. It's an excellent approach.

What do you know about the medication you're taking? They know right off the bat, they need to tell them something, as opposed to a piece of paper in front of you. The guy's running late anyway. His car is double-parked. You've got to be kidding me. I don't need counseling, marks the block. They've fulfilled their obligation. They fulfilled what the state allows them to get by with in the implementation of OBRA '87.

It became convoluted in my perspective, and I think in NABP's. If the law was implemented the way I talked about it, where every pharmacist and every owner allowed the pharmacist to do this, every chain drugstore allowed the pharmacist to do this, to be very proactive and counsel patients, we would have a lot less problems than we have today, but a lot of that still is being resisted, although more and more -- I'll say, chain stores because they are the biggest pharmacies today. The mom and pop stores are gone, basically.

They have to develop an attitude that that is worth spending the money on to allow the pharmacist to counsel the patients and not go through this what I call "shell game" with a piece of paper. So, there is a law. It is being implemented, but it could be implemented much more stringently to the benefit of the patient if it's allowed to happen, and I don't think it will happen over the next short period of years.

DR. GALSON: Okay. The next question is, is there a way for a pharmacist to determine whether the patient is taking another drug obtained from another pharmacist across town? If not, is there something like this enforced?

DR. MAY: Yes. Well, I'd have to say yes partially. In many drugstores today, including a lot of the chains, they have a computerized entry system, where, particularly if you're getting all your prescriptions filled at, say, Giant in this area or CVS, in their computer, you go to one store, you go to multiple stores, all the drugs you're taking are going to show up in that print-out, and when a pharmacist fills a prescription, he puts it in the computer to have a label generated, he's going to have that sheet printed out right away that has all the information on it.

They're not stacked up in a pharmacy in a full amount. That's generated by the printer right as that prescription's being filled. The label comes out and that sheet comes out. The information is developed by other retail pharmacists. It's developed by information groups that have the data. All of that comes out of the printer, a computer-generated printing system.

So, the information is there, and it can get to the patient, if the pharmacist does the proper role of counseling.

DR. GALSON: Okay. Of course, every pharmacy chain has got their own system. They're not linked together.

DR. MAY: The fact of the matter is, in this country today, 95 percent of all pharmacies -- this is year-old data. I don't know what -- 95 percent of pharmacies one year ago had computer systems in the pharmacy. Even small pharmacies realized they had to have this system. They just buy the software. They buy the system. It costs $2 or $3,000, but they have to have it basically if they are to operate. It prints out the material safety data sheets.

DR. GALSON: No. I'm saying that Rite-Aid doesn't talk to CVS, doesn't talk to --

DR. MAY: Oh, they talk through the NACDS, which is the National Association of Chain Drugstores.

DR. GALSON: The computer systems aren't linked.

DR. MAY: Oh, right. No, their computer systems aren't linked chain-to-chain, no.

DR. GALSON: Okay. The other question is, does NABP believe that counseling should only be given to the drug prescribed or should a pharmacist question the individual on what other drugs they're taking and provide counseling? I think you really answered that already.

DR. MAY: Well, let me just add one thing. That is done by the fact that in a chain particularly, knows all the drugs being taken. They see that a certain drug may be contraindicated because they go to multiple physicians for one. Everybody doesn't go to the same cardiologist that go to a GP that go to a dermatologist.

There are already prescriptions. They're all getting filled by, say, Giant because they're loyal to that. That will become known to the pharmacist, that they're getting this drug, this drug and this drug, and there are one or two or three contraindications, so they shouldn't be taking it.

They will then call the doctor and say are you aware that Dr. So and So is prescribing this? Oh, my God, no. Got to get him off of that, and there is an interaction to stop that from happening. It's on-going. It's very effective. It should be increased in all pharmacies but yes, that is happening.

So, including the inclusion of over-the-counter drugs because they ask the patient, when they get them as a new customer, what other drugs are you taking by prescription, what other drugs are you taking over-the-counter. They give them a sheet of paper. They fill it out and that data is entered into that company's computer, and all of that's in there. They're taking these over-the-counter.

Now, the patient can say oh, I don't want him to know what I'm taking over-the-counter because the doctor may not know all of them, but it's asked by chains. It's asked by pharmacies and that data is entered into the computer system, and it's all there, including software that has warnings for overdoses, warnings for drugs that are contraindicated and interact with each other. They get a message coming out. These drugs should not be taken together. They then call the doctor, call the patient. All those things are in play today.

DR. GALSON: Okay. If there's time, I'll read the statement quickly. There is a drug recognition officer in the audience, and he wanted folks to know that in the program, most states use urine, not blood. Only nine states have a blood demand, and the DRE determines the impairment. The body fluid confirms the drug.

DR. ELLINGSTAD: Okay. Thank you, everyone. We're right on schedule again.

What we'll do now is take about a five-minute stand-up and stretch break in order to switch our panels. I'd like to remind all of the witnesses who have presented that we -- if they have not turned in the copies of their presentation, we need them, and if they'll check with the people at the desk out in the lobby, we'll collect that.

Thank you.

(Pause)

DR. GALSON: Okay. I think we're ready for our last panel for the day, our fourth panel, Members from the Military, and I want to welcome Colonel Saenger and Captain Fulton, respectively, from the Air Force and the Navy.

We've been starting from the right side. So, Captain Fulton, if you want to start first.

Witness Panel IV - Military

CAPTAIN FULTON: Thank you.

Good afternoon, and I guess it's almost evening. But I'm Captain Dwight Fulton. I'm the Director of Aerospace Medicine for the United States Navy.

As such, I am the medical representative for really only one of the operational arms of the U.S. Navy and am best able to focus my comments therefore on how we in naval aviation address the issues outlined in the goals for this particular meeting, those goals being essentially data available to define the role of impairing medications in accidents and related issues, how the potential for medications to cause impairment might be best assessed, and then how this risk would be most effectively communicated to the public or, in this case, to our naval air crew.

As relates to data available to define the role of impairing medications in accidents and related issues, accidents involving naval aircraft trigger a safety investigation. It is conducted by our Aviation Mishap Board, made up of personnel from within the mishap squadron and from without.

Included in these investigations is the flight surgeon assigned to that specific squadron. The flight surgeon's responsibility is to identify any medical or human factors that may have been causative factors contributing to that particular mishap.

Part of the flight surgeon's responsibility is to conduct drug testing for prescribed narcotics or other non-prescribed illicit medications, to conduct a review of any involved air crew medical records, to obtain 72-hour histories on all involved air crew, and to conduct a physical exam on any of the air crew that were involved in that mishap.

If, in the course of this work-up, it is found that the air crew was on any medications, it is also that flight surgeon's responsibility to determine if the side effects or the therapeutic effects of these medications could have contributed to that specific mishap.

As an aside, in many of our operational sites, the cognizant medical treatment facility completes an accident report on anyone who presents with injuries related to a specific accident. These reports are usually maintained locally, unless the accident exceeds an indicated number of lost work days, and then the report gets submitted up the chain of command to the Naval Safety Center. Therefore, the Naval Safety Center is a repository for some limited number of accidents that meet specific criteria.

These non-standardized accident reports generated on the local level will usually ask for any medications that the person involved in the accident may have been taking.

As relates to how the potential for medications to cause impairment might be best assessed, in naval aviation, there is no physical testing process in place to assess the potential for medications to cause impairment in air crew. There was some work done at the Naval Aeromedical Research Lab in Pensacola, Florida, in past years, looking at establishing a battery of tests to assess the cognitive effects of different medications recommended for naval aviation, but to date, no specific battery of tests has been approved.

Currently, medications that are considered for use in naval aviation are reviewed by the Aeromedical Advisory Council at the Naval Aerospace Medical Institute in Pensacola, Florida. Information considered in this review process includes any recent medical literature and science regarding the potential side effects of the proposed medication, the known uses of the proposed medications in the civilian and military communities, and the current stand of our sister services on these particular medications.

As relates to how this risk would be most effectively communicated to the public, and in this case, our public is naval air crew, in naval aviation, it's our flight surgeons and our aviation technicians who are messengers out there in the fleet.

The flight surgeons are trained on the medications that are compatible with naval aviation and are responsible for monitoring their air crew to ensure that there is no use of undesignated medications. They do this through spending time with the air crew in their spaces and through annual assessment of an air crew's medical history and physical status.

During these annual assessments of medications, air crew are reminded that they are not to use any medications without the flight surgeon's consent.

In addition, a pilot is reminded that if he is seen by a physician other than a flight surgeon, he is grounded until a flight surgeon has reviewed the medical care and treatment provided by that other physician.

In addition, the flight surgeon conducts safety briefs in the squadron spaces, and the issue of medications is one of those issues that's briefed on a regular basis.

This naval policy on medication and air crew is further reinforced by our line community in our OPNAV Instruction 3710.7R, which is the Guidance on General Aviation Policy. This guidance reinforces that an air crew man should not take any medications, over-the-counter or otherwise, without the explicit approval and supervision by the flight surgeon.

Again, I'm not really astutely aware of how medication is used, use is monitored and controlled with other forms of transportation than the Navy, but I would be glad to research and provide any information to you on these specific areas, if requested.

DR. GALSON: Thank you very much.

The next speaker is Colonel Arleen Saenger from the Air Force.

COLONEL SAENGER: Good afternoon.

I'm Arleen Saenger. I'm the Chief of Aerospace Medicine in the Air Force Office of the Surgeon General. As such, I am analogous to Dwight and that of the Director of the Aerospace Medicine Program for the Air Force.

Our programs regarding aviators are very much analogous and essentially the same as they are for the Navy. So, I'll touch briefly on that, but I'll also touch a bit on what ground safety data I was able to get from our Air Force Safety Center.

I'm going to address the two specific key questions. How has the U.S. Air Force addressed the use of medication by transportation operators, and how effective have our efforts been?

Additionally, what is our experience in assessing, communicating and preventing the risk of sedating or impairing medications in vehicle operators, and how are our applicable laws or what we would call instructions or regulations enforced?

First, aviation and then ground. As I said, the mishap investigation for aviation mishaps is essentially the same for the Air Force as it is for the Navy. So, I won't go into that in any detail.

Our Air Force Instruction on Medical Standards specifically addresses the use of medications, both prescription and over-the-counter, by air crew and what we call special duty personnel. For instance, air traffic controllers and others.

Medications are not allowed to be taken without the specific permission of the flight surgeon, just like for the Navy. There are certain medications which we can waiver for our air crew use which the local flight surgeon can allow the air crew to use once a period has passed so he can determine there's no adverse side effects. There are other medications where you have to request formal waiver from higher Headquarters.

In no case is the aviator allowed to perform flight duties while taking a medication that would be sedating or impairing.

Medications that are sedating or impairing result in a grounding, a temporary grounding or NIF duties, not to include flying action, and the aviator cannot go back to flying duties until cleared by the flight surgeon.

As with the Navy, we also require the flyer to report to the flight surgeon's office after being seen by any provider outside of the flight surgeon's office. They are to consider themselves grounded until otherwise cleared by the flight surgeon.

As for education on the use of medications, like the Navy, this is a frequent briefing topic with our aviators. We drill it into their heads at every opportunity. It's a mandatory briefing item at squadron safety meetings. It is discussed in encounters in the squadron informally. It's discussed in the encounters in the flight surgeon's office, both by the doctor and by the technicians, the aeromedical technicians. So, we educate, educate, educate.

We feel it's been very effective in our Air Force aviator population. There have been no mishaps, aircraft mishaps in the Air Force where the use of medication, prescription, over-the-counter, licit, illicit of otherwise, has been found contributory.

How do we enforce it? Again through mostly education. We know our population. We have a very defined population that we see on a daily basis. We know them. We know their families. We know the squadron, and education is a key to that.

The commander can take administrative action if anybody is found to be self-medicating without reporting to the flight surgeon. I don't have any data on how often that has ever happened, though.

Mishap data. We do toxicologic testing on all aircraft mishaps, regardless of cost, in terms of cost of the mishap, that is. We do screen for carbon monoxide, ethanol, amphetamines, barbiturates, benzodiazepines, cocaine, opiates and bencyclidine. We also screen for various typical over-the-counter and prescription medications, too, on a varying basis.

Ground mishaps are a different issue. We've got a fairly robust database for aviation mishaps, but for ground mishaps, it is a different issue, as was noted in the NTSB Board recommendations from January of 2000.

There is a manual that addresses wheeled vehicle drivers. It's an Army field manual and an Air Force joint manual. That is the only regulation or instruction that we have that governs wheeled vehicle drivers, and the only note in that instruction is a note to a table where it states, "The driver is responsible for notifying your supervisor or NCO of any change in your status; for example, inability to drive due to a physical condition." So, we really don't have any regulations or rules, other than that, governing medication use by ground vehicle operators.

Education is problematic, also. There is no systematic education for ground vehicle operators. We rely solely upon the medical provider and the pharmacist in educating the patient on the side effects of the medication that they're being prescribed or that they might be buying over-the-counter.

How effective is very difficult to determine due to the policy issues of not having any rules governing it and relying solely on provider and pharmacist education but also on database issues.

Currently, the Air Force collects data on ground vehicle mishaps only for Class A mishaps, and those are mishaps which involve a total cost of a million dollars or more, a fatality or a permanent total disability.

The database that we do have has a very limited search capability. Nonetheless, the Safety Center did a review of about 12 years of motor vehicle Class A mishaps. Almost all of these involved fatalities. Of 986 Class A mishaps during that time, there were only two in which drug use was found to be contributory. One was for cannabis and one was for cocaine. However, this is not complete data.

Testing is not required. In fact, in only 55 percent of these cases was testing done on the involved driver. Testing is only required if, in the opinion of the police officer on the scene, is necessary or if the member's commander directs it.

Enforcement's also problematic, unless there is some legal military action to be taken on the part of the commander, and we have no data regarding numbers or anything of that nature.

For our future directions, the Safety Center has recognized there's a very large knowledge gap here, and we are developing a program to require human factors investigation on all mishaps, air and ground, all classes, all cost classes. So, everything ranging from a $2,000 mishap with a minor injury all the way up to a million dollar mishap or loss of life, air or ground, will have human factors investigation, and as part of that, it will include drug testing, but that's being developed currently.

There will be a database that will go along with that, the information systems, to support that, but it's a future thing. Right now, we don't have a very good ground mishap reporting data collection system.

That's it for the Air Force. Glad to take any questions.

DR. GALSON: Great. Thanks very much.

We're going to first start with questions from the Technical Panel, and Dr. Andreason, do you want to start?

Questions from Technical Panel/Parties and Discussion

DR. ANDREASON: Sure. Thank you very much for your presentations.

First of all, I just wanted to say that my dad was an Air Force officer in a fighter squadron. So, some of my questions will be based on his experience.

It's my understanding that you do have a list of acceptable drugs for flight crew. How did that list come about?

COLONEL SAENGER: It's evolved over the years. It also has evolved somewhat as the Navy has, where we get consultant input. We pull the other services, our sister services in the U.S. and also our allied services for their experience with the medication. Literature research. But a lot of it is simply based on a body of usage, and those drugs are specifically listed in our Air Force Instruction 48.123, which is Medical Standards.

DR. ANDREASON: So, you have a review board that kind of reviews these as they come out, is that correct?

COLONEL SAENGER: Not as the drug comes out, no, but if somebody in the field raises the issue or if one of the major command flight surgeons raises the issue of this might be something we'd want to consider allowing for use in air crew, then the background research and the decision process starts.

We have an Aerospace Medicine Corporate Board, which is composed of all the flight surgeons, the command flight surgeons for the various Air Force major commands, along with individuals from the Aeromedical Consult Service at Brooks Air Force Base and the School of Aerospace Medicine at Brooks Air Force Base, and it becomes a joint decision, based on research, and sometimes it's just gestalt.

DR. ANDREASON: Well, that pretty much answers my question, but maybe to beat the horse a bit more. Could you perhaps take me through some hypothetical steps about how, say, a new ostensibly non-sedating antihistamine might make it on to this list?

COLONEL SAENGER: That was done specifically with a literature review, an extensive literature review. Part of the problem with literature review is we're concerned with some neuropsychiatric side effects and some subtle impairing side effects that are not necessarily addressed during the testing for the FDA for approval to use it.

So, it's extensive literature review and consultants, specialty consultants, subject matter experts. We gather their inputs, and we go over the results of that and debate it a lot, and then we come to a thumbs-up/thumbs-down decision and take a vote.

DR. ANDREASON: So, now in the United States, because of the user fee initiative, drugs are often released first in the United States instead of other countries. There's not a lot of data outside of what's in the labeling.

Does that mean that, say, a new antihistamine might not make it on to the flight crew list until this type of research was done in the academic community or, say, as part of a Phase IV commitment?

COLONEL SAENGER: Yes. We wouldn't jump on something the day it was released. We would want to see at least a year or preferably more of post-marketing data that we could look at.

CAPTAIN FULTON: One other thing to comment on, too, is that when a medical -- usually or at least in terms with the Navy, when we start a particular medication or introduce a new medication, it's a gradual process to bring the medication on.

A lot of times, we just don't bring it on and then, okay, you can start using this medication carte blanche. What we do is we waiver some of our individuals to be on these medications for a particular period of time. By being on a waiver, then they're closely -- more closely monitored by the flight surgeons than a drug that was not considered disqualifying and could be used on a regular basis.

So, they'll watch for a period of time, and then, after they've -- that medication, we see in the air crew that it hasn't caused any significant impairment or side effects, then that drug will be upgraded to a not-considered-disqualifying drug, and those individuals can then use it without having a waiver, as long as it's prescribed by a flight surgeon.

COLONEL SAENGER: It's very much like that in the Air Force, too.

Another thing that we do, I believe, that Navy does, also, is we'll start with the back-end, so to speak, of the aircraft and move forward, and we may allow a medication used with or without a waiver, but with a waiver usually, for a load master or an air battle manager, and then, after we gain experience with it at that level, approve it for use in our aviators.

DR. TEMPLE: These things are done systematically? There'll be a servicewide decision that the flight surgeon can allow use of something, so everybody will know about it, and do you record the results?

COLONEL SAENGER: Yes, there is.

DR. TEMPLE: It's not just local option?

COLONEL SAENGER: No. No, it's not just local option. We'll publish a policy memorandum, and then when it comes time to change the instruction, we'll add it.

DR. TEMPLE: And have you sent your lists to us, and can you?

COLONEL SAENGER: Yes, I can.

DR. GALSON: Let me just exercise the prerogative of the chair here and ask you, what's the status of the sedating antihistamines on these lists?

COLONEL SAENGER: We allow non-sedating with waiver.

DR. GALSON: Sedating?

COLONEL SAENGER: No.

DR. GALSON: Under no circumstances?

COLONEL SAENGER: Under no circumstances.

DR. GALSON: You wouldn't want to say which or which, would you?

COLONEL SAENGER: Allegra and Claritin.

DR. GALSON: Okay. Sorry to interrupt there. Please continue with the Technical Panel questions.

DR. TEMPLE: I'm sure we'll be interested in the list, and, you know, any other on-the-way things that you're working on. I mean, how to gain information about this sort of thing is part of the problem here. So, how you do it in a relatively controlled environment is going to be very interesting.

CAPTAIN FULTON: It's interesting because I just came back from a standardization meeting over in England regarding all of the English-speaking Air Forces. The British were present, the Australians, New Zealand, Canada, and all the services from the United States, and one of the things that -- one of the information-gathering things we're going to be doing over the next year is identifying what the processes are that the different services have to evaluate these medications, and where they're going with these particular processes, because right now, I don't think any of the services, at least based on the meeting that I was at, have a systematic process by which we do testing on the particular medications, tox screens, although I believe that the Air Force has a process that they're working on and to bring into action, and I know that the Navy, like I said in my introductory remarks, looked at a process several years ago, but I think that that kind of died, and there's no process in place right now.

COLONEL SAENGER: What I was referring to is a process for doing what we're calling "one of" occupational evaluations. The issue is we don't have the resources to do systematic research, as we did, for instance on my Centapro, in order to determine whether that was allowed in air crew, in pilots, or not.

If we've got an aviator whose not had an adequate response to an allowed medication for his or her condition, and you try a medication that's not on the list, and it works really well, how do we assess them for allowing them to have a waiver or not?

The proposed process that we have, it's due to start fairly soon now, the Consult Service, I don't believe we've had our first patient down there under this protocol yet, is to bring the individual down off the medication, do the neurocog testing. If they are in fighters, put them in the centrifuge, put them back on the medication for a period over the weekend, retest them because we want to know before and after.

It's an N of 1, but for that individual, it's a mechanism for allowing them to fly on that medication that's not currently on the air crew waiver list.

DR. ANDREASON: They do that down at Brooks?

COLONEL SAENGER: Yes, at the Aeromedical Consult Service, Brooks.

DR. ANDREASON: Are there any drugs that are considered impairing that are not necessarily sedating that are not allowed in the Air Force?

COLONEL SAENGER: Impairing from a psychological standpoint? Yes. We tend to think of impairing in terms of neurocog, but there is G tolerance issues that we both have to address.

DR. ANDREASON: Neurocognitive. That's kind of what we're driving at. So, in that sense, it would be blood loss or blood profusion problems?

COLONEL SAENGER: Yes.

DR. TEMPLE: Wait a minute. The beta blockers have a number of things they do that might make you think a person couldn't respond to an emergency.

Are there any things that affect neurocognitive function that are not sedating that are on your list? I think that's the question. That's what they wanted to know.

CAPTAIN FULTON: Without having a list sitting here right in front of me to answer that specific question, I can't.

DR. TEMPLE: Okay. You can imagine people would worry about amphetamines, not because they sedate you but because they distort the way you react to things.

COLONEL SAENGER: Yes.

DR. GALSON: Does NTSB have any questions?

DR. GARBER: Yes, and I know this is going to sound strange to my military colleagues to even ask this question, but I assure you that from a civilian perspective, it is meaningful.

The military prohibits the use of all medications for their air crew, unless those medications have been specifically evaluated and determined to be safe for their use.

Why has the military taken that approach; that is to say, prohibiting everything and allowing only a few things, as opposed to allowing everything, unless it has been proven to be impairing?

CAPTAIN FULTON: I'll take a stab at that one, okay, but (1) I think it gives us a little bit tighter control over what medications individuals take, you know, and I think that, you know, if we allowed everything, if we allowed everything, we wouldn't have any control over what medications are taken.

DR. GARBER: So, you would be civilians?

COLONEL SAENGER: We would be civilians. I suppose it reflects the different philosophies. It's safe until proven unsafe or it's unsafe until proven safe, and if we allowed everything, it would be an issue just the span of control to allow everything and then have to prove specific things on faith in order to disallow them. It would be a lot harder to do than just say no, we're going to disallow everything, and then what we can prove through experience, research, whatever to be safe is more approachable, more obtainable.

DR. GARBER: Do you find it odd that a different approach is used in the civilian community?

COLONEL SAENGER: No. There's lots of other examples of that, too. Plus, we have a more controllable population. When you know your population, and it's very defined, and you control their medical records, and you see them at the club, and you see them at the commissary, you can -- you have greater span of control and greater span of influence. You're dealing with a totally different population on the civilian side.

DR. GARBER: Dr. Temple reminds me that we actually -- that from what you've told us, that the military ground approach is actually very similar to the civilian approach throughout transportation.

Is there a reason that the military uses a different approach for their ground personnel than they do for their aviation personnel?

COLONEL SAENGER: Well, being the Air Force, we tend to emphasize aviation, which is, you know, the ground is still important. I think it just hasn't been given the attention which is why the Safety Center has brought the issue up through their line channels and through the Air Force Surgeon General saying this is a major safety issue, also, and we need to start attending to and dealing with this.

The Army may have some more data on ground, but, unfortunately, he's not here. So.

CAPTAIN FULTON: I think one of the other issues to look at, too, is when -- I'm not sure about the Air Force on this, but I know with the Navy, when we have a mishap, we look at all the people that may have been involved in that mishap, okay, and so, you know, for us in a lot of circumstances, that includes ground crews, and that includes the people who are from those areas.

So, if there's a mishap investigation done, and we do toxicology evaluation on the pilot, well, we may also do toxicology evaluation on the air crew that worked on that airplane to make sure that that wasn't a causative factor that's involved in that particular mishap, and the other area that concerns us very much in the Navy obviously is the flight decks on aircraft carriers, where we have a large number of people, and as a matter of fact, we're working on the process now and trying to include the process by which we monitor the people that are on the flight deck and what medications those individuals are taking.

DR. GARBER: So, I think what I'm hearing is that as with the civilian community, this is an area of emerging concern for the military services?

COLONEL SAENGER: And the Air Force does check on aircraft mishaps, if there's a ground personnel or air traffic control personnel, maintainers, flight line people involved. They are tested, also.

DR. GARBER: Thank you.

MR. KOTOWSKI: In the toxicology evaluations from mishaps, the prescribed test, is it blood or urine?

COLONEL SAENGER: Blood and urine, depending. I'd have to look at the table to see which is which.

MR. KOTOWSKI: And is there a preference over one type of test versus another?

CAPTAIN FULTON: Not that I know of. I think that to be honest, all of our blood tests, most of what we send off are blood work-ups through the Armed Forces Institute of Pathology, and they run all of our blood tests.

COLONEL SAENGER: And for air mishaps, it's the same.

MR. KOTOWSKI: And then the results of those blood tests, are there cut-off limits that are established as to whether or not it's a positive reading or is it any trace amounts that's recorded as a positive reading?

COLONEL SAENGER: I'm not sure of the answer to that either, but I know they report the amounts. Whether there's a cut-off, I don't know.

CAPTAIN FULTON: We can find that answer out for you.

DR. GALSON: Okay. Why don't we move on to the parties' questions, starting with the Union Table? Any questions for the panel?

MS. HEAD: This is for Colonel Saenger. You talked about the self-identification requirement for ground operators. You spoke about that you had a manual, and you said that they only require it for ground operators, that they notify if they have a change in their physical condition.

How is that requirement enforced? Is it -- what happens to an operator if they do self-identify or what happens if they fail to self-identify?

COLONEL SAENGER: We don't have a database on that, so the data's not being collected, but I can tell you that if somebody was involved in a ground mishap, and they had been taking a medication that impaired them or if they had a physical condition that impaired their ability to drive or their judgment, and they had not identified that to their supervisor, then you could take UCMJ legal action against them, but I have no data on whether numbers have been done or anything.

MS. HEAD: Do you know if they're given any guidance for what it means to have a change in physical condition? Are they given any guidance as to what medications may -- if they're taking Claritin or something.

COLONEL SAENGER: Not that I know of, again because we don't have a systematic education program for ground vehicle operators.

CAPTAIN FULTON: One thing that I will mention is maybe -- I'm not sure that this is unique to the military, but one thing, most military doctors really get ingrained, and if they see a patient in the clinic, one of the first questions that they ask them before they leave that clinic is what do you do? What is your job?

Because it's so imperative that we understand what that job that they're doing because that really affects a lot of times the type of medication that we choose to put them on or whether we send them back to limited duty or whether we send them back to full duty.

Because certainly, I think that the thing that scares me most is when civilian providers see our military folks, and those civilian providers don't think to ask the question of what do you do, what is your job, because they'll send those people back on medications that I as a military physician wouldn't send that person back to do that particular job.

COLONEL SAENGER: Same with the Air Force.

DR. GALSON: Okay. Any other questions? Yes?

CAPTAIN POPIEL: Colonel Saenger, Captain Popiel, Randy Popiel, Allied Pilots. Just a couple quick questions, more of a clarification.

Are all the drug and alcohol tests done in the military, are they done post-accident or do you have a random screen?

COLONEL SAENGER: We have random drug testing in the military, also.

CAPTAIN POPIEL: In regards to the flight surgeon and his authorization to prescribe medications to your crew members, do they generally -- do your flight surgeons generally stay within the prescribed list that the Armed Services provides to them or will they vary? Will they make the initiative and approve something other than what's on that list?

COLONEL SAENGER: They'll generally stay within the list, and if an approved medication doesn't work, and they have to put them on a medication that's not on the approved list, then they would have to ground the flyer and request a waiver.

CAPTAIN POPIEL: Are any forms of antidepressants allowable and currently approved?

COLONEL SAENGER: No, not for the Air Force.

CAPTAIN FULTON: Not for the Navy.

CAPTAIN POPIEL: Are any sleep medications approved for use by crew members on required rest periods?

COLONEL SAENGER: Yes. Yes, we do. We have ground use of Senota, Ambien, and sorry, I'm blocking, but one more. We do have three. There are three sedative hypnotics that are allowed for ground use during crew rest for the air crew.

CAPTAIN POPIEL: Is there a clearing period after the crew member has taken the medication?

COLONEL SAENGER: There is a bottle-to-throttle time for each. For Senota, it's four hours. For Ambien, it's eight, and Restoril, it's 12.

CAPTAIN FULTON: And it's the same -- the Navy -- we call them performance maintenance drugs, and it's Restoril and Ambien are the ones we use, and there is a period after which they can't fly.

COLONEL SAENGER: We call those operational drugs, too, instead of therapeutic drugs.

CAPTAIN POPIEL: So, your time for your crew member to operate the equipment would be probably shorter than what the FAA would allow? Is there a general rule on the clearing drug would be twice the dosage time?

COLONEL SAENGER: We base it on roughly twice the half-life of the medication. That was a very recent change. We just changed that last month for the Air Force. It had been 12 hours flat before.

CAPTAIN FULTON: Yes, and I'm not sure what the times are, what the absolute times are after they've been taking those medications. I think it's six to eight hours.

CAPTAIN POPIEL: Thank you.

DR. GALSON: Great. Transport Industry, do you have any questions?

DR. FAULKNER: Yes. Tom Faulkner from the Air Transport Association, and also I'm a flight surgeon in the Navy Reserves. So, I thank you, first of all, because in the military, as I was trained, you spend at least half your time in the squadron spaces getting to know your pilots, and the pilots had no choice but to see you, versus when they get out in the civilian world, let freedom ring, and the old adage is the pilot's physician and their aviation medical examiner will never meet.

So, it's kind of -- when we talk about a list and things like that, it also goes into the culture in the military versus out there in the civilian world. It may not be quite the right thing to chase with a list for the civilian population.

Can either one of you comment on your service's stance on supplements, and why you have that stance on supplements?

COLONEL SAENGER: For the Air Force, we have specifically prohibited ephedra compounds in air crew and special duty personnel. Regarding Air Forcewide, I know that there's a DoD Tri-Service Working Group with FDA and CDC and perhaps some of you are on that, also, that is looking at the herbal supplement issue, but there's not been a DoDwide directive yet, and there's not been an Air Forcewide directive on nutritional and herbal supplements for all members.

CAPTAIN FULTON: I've just been looking at a string of e-mail on this, and that's the -- you know, and there's a lot of questions coming up as to why not, and I guess that, you know, earlier, Arleen mentioned, you know, I -- the Navy stance still is, and we stick by our stance, is that we do not allow use, unless it's -- they've talked to the flight surgeon about it.

The flight surgeon is aware that that specific -- that particular individual is on a particular medication and is monitoring that medication extremely closely. Certainly there's certain drugs, like anabolic steroids and those things, you know, that are not going to be approved, but again it has to be monitored by a flight surgeon if to be used at all.

COLONEL SAENGER: That's really the same for the Air Force. We do have a little trifold information pamphlet that we have available for the docs. We tried not to take a -- the names have changed so often of those compounds, that to put a name -- a list of names against it, we put it out by those that have been generally, not to use this phrase deliberately, but generally recognized as safe, and a list of those that we know that there may be problems with in terms of performance and safety issues and provide that guidance to the flight surgeons for them to use when they're talking to their flyers and folks about the use of supplements, and, of course, we're supposed to ask that question with every single patient encounter, not just what medications they're taking but what supplements and herbal and nutritional supplements they're taking.

DR. GALSON: Okay. I think we want to move on, looking at the time here.

The Consumer Healthcare Products Industry?

DR. SOLLER: Bill Soller, CHPA. We have no questions.

DR. GALSON: Okay. Advocacy Table?

MS. TARNEY: We have no questions.

DR. GALSON: Professionals, the sleep people?

MR. DROBNICH: Just one quick question to clarify. Darrel Drobnich, National Sleep Foundation.

As your guidelines stand now, your rules and regulations don't apply to the flight deck crew or support personnel, maintenance and so forth?

CAPTAIN FULTON: Well, I'm not going to say that they don't apply because they really do apply. Our flight deck personnel are -- the problem is, is that -- the main problem with that is we don't have as tight control over the flight crew with flight surgeons as we would like to have, okay, and we're getting tighter control over them with flight surgeons now.

As a matter of fact, we just went out with a message, Navy message again stating that a flight surgeon has to review flight deck screens that are done on anybody that works up on the flight deck, and that if an individual is put on -- that works on the flight deck is put on medications, it has to be reviewed by a flight surgeon to determine whether that individual should be working up on the flight deck with that particular medication.

MR. DROBNICH: So, --

CAPTAIN FULTON: So, we are trying to tighten those standards.

MR. DROBNICH: So, a mechanic or a flight deck personnel would have to get approval before they can be put on a medication to continue work on the flight deck?

CAPTAIN FULTON: We would just like the flight surgeon to evaluate the medication he's on to determine it's okay for him to work up there in that position.

MR. DROBNICH: So, it's not the same waiver process as the pilot would have to go through?

CAPTAIN FULTON: No. It's a different -- it's not as stringent a process as we do with the pilots.

MR. DROBNICH: Okay. And my second quick question is actually following up on what Dr. Andreason mentioned about certain drugs, like hypertension drugs, that might cause insomnia or have nightmare problems with that, that might impair performance the next day.

How is that handled by the military? Drugs that -- like hypertension -- I would imagine -- is that an approved drug?

COLONEL SAENGER: We have multiple anti-hypertensives that are approved. Generally, what we do is we require a mandatory grounding period before you ask for the waiver, and it ranges anywhere from a week to four weeks, and it's precisely to address those issues that just one or two doses might not tell you.

MR. DROBNICH: And I guess that would be followed up with interviews with the patient, to say are you having any sleep problems associated with this drug?

COLONEL SAENGER: Exactly. Any of the aeromedically-significant side effects.

CAPTAIN FULTON: When a -- and I know this works the same in the Navy and the Air Force. When an individual's put -- is grounded, he has to be put back up by a flight surgeon and that involves a face-to-face with the flight surgeon in order to be able to be put back on a flight status, and specifically addressing (1) is the condition that he was grounded for and (2) if it were medications he was put on, how are you doing with those specific medications? If you're doing okay with it, we can let you go ahead and continue flying.

MR. DROBNICH: Thank you.

DR. GALSON: Okay. Government Table?

MR. CLARKE: I just have a couple questions, and it's by way of education for my benefit more than anything else.

How many folks typically does a flight surgeon have oversight of? 10s? 20s? 100s?

COLONEL SAENGER: A typical flight surgeon at a clinic or a hospital would enroll up to 750 and that includes the active duty member, plus/minus family members. Some places have more family member involvement than others. So, it's dozens and dozens.

MR. CLARKE: And, I mean, in terms of aviators, people who are in aircraft either as pilots, co-pilots, aviators, what have you, anybody that's in a flight status, how many of those kind of people do they have oversight of?

The reason I'm asking is, you were mentioning that they have intimate knowledge of these people. So, I assume it's a relatively small number?

COLONEL SAENGER: It's a fairly small number, and it depends on the squadron, is it a transport squadron or is it a fighter squadron, as to how many pilots and other air crew members will actually be in that squadron, but generally speaking, each aviation squadron in the Air Force has a flight surgeon that is their doc.

MR. CLARKE: And so, how many flyers typically are in a squadron or how many air crew are in a squadron?

COLONEL SAENGER: A hundred or 200 or, you know, it varies. You might actually have two squadrons that you care for, depending on how short the base is.

MR. CLARKE: So, they can have intimate knowledge of each one of those individuals?

COLONEL SAENGER: Yes. We've got a very defined population that we know very well.

MR. CLARKE: In the event that a flyer or an air crew member for whatever reason has to take one of these drugs that are not on the list, does that automatically disqualify them from flying?

COLONEL SAENGER: It does.

MR. CLARKE: So, when they go see the flight surgeon, what happens then? I mean, is there any conditions under which the flight surgeon can allow that person to fly?

COLONEL SAENGER: If it's a sedating medication or --

MR. CLARKE: Any medication.

COLONEL SAENGER: Well, if it's on the list that the flight surgeon may allow them to fly as long as --

MR. CLARKE: No, no. No, no. You have a list that you've approved.

COLONEL SAENGER: Yes.

MR. CLARKE: So, everything else is not --

COLONEL SAENGER: We're dealing off the list?

MR. CLARKE: Yes, everything is off the list.

COLONEL SAENGER: They would have to be grounded while they were on the medication, and if it was for a temporary condition, as soon as they are finished with the medication, and the condition has resolved, and they see the flight surgeon again, and they get --

MR. CLARKE: Is that --

COLONEL SAENGER: -- returned --

MR. CLARKE: -- for any member of the air crew?

COLONEL SAENGER: Yes, it is.

MR. CLARKE: The front to the back of the plane?

COLONEL SAENGER: Yes, it is. If they're an air crew member or special duty personnel, also. So, that includes people who jump out of airplanes, combat controllers, air traffic controllers.

MR. CLARKE: And there's no differentiation by type of aircraft or type of operation or any of that kind of thing?

COLONEL SAENGER: No. We do have some differentiation, though, in terms of -- sometimes we will waiver a medication for use only in non-high-performance aircraft. We won't put them in single-seat fighters with it.

MR. CLARKE: All right. Well, that was my next question. Is this concern based primarily on the nature of the environment in which these people are operating?

COLONEL SAENGER: Yes, it is.

MR. CLARKE: In other words, it's a relatively very severe --

COLONEL SAENGER: It's an operational risk management process that we go through, yes.

MR. CLARKE: Does that logic then follow over why you don't apply the same thing to your ground crews, that the operational environment doesn't put the person in as much risk?

COLONEL SAENGER: Actually, no. I think it's simply been neglected. It's an emerging concern as expressed for the military as well as for yo'all.

MR. CLARKE: Okay. Thank you.

CAPTAIN FULTON: If I could make just one other comment? Excuse me. Real quickly.

DR. GALSON: Certainly.

CAPTAIN FULTON: It's background. You know, as I think Arleen says, it is something that's emerging, you know. We're taking more of an interest in the ground crew. I mean, we do have in place -- there's a DoD instruction that people that operate heavy machinery or they operate have to go through a screening. You have to go through a screening process by a physician before they're allowed to operate that particular machinery.

So, in that respect -- and they are educated at that point, in that point on the visit, about medications and about the importance of letting someone know that they're on those particular medications as part of that screening process, but then it's the follow-on with the ground crew that we really don't have down well.

MR. CLARKE: I guess from an operational point of view, does this have any limiting effects on your ability to perform your missions? I mean, at any one period of time, let's take an aircraft carrier, where people are in close confined spaces. You get the flu or something running through the place.

What does that do to your operational capability?

CAPTAIN FULTON: If people have the flu, they're grounded until they're over the flu.

MR. CLARKE: Do you get large numbers of folks on the ship having the flu?

CAPTAIN FULTON: Well, that's one of the things that we have to deal with on a day-to-day basis, you know. An operational tempo is obviously going to influence some decisions that are made out there by the commander and by the flight surgeon, but at least we know that in that situation, whatever is done, people are being monitored.

MR. CLARKE: So, there is some latitude?

CAPTAIN FULTON: Well, it's not a whole lot, but operational commitments sometimes requires it. I mean, before, we never considered using the performance-enhancing drugs, the performance maintenance drugs, okay, but understanding that where there's a high operational tempo, there may be a requirement to use those particular medications in order that those people get the rest that they need so that they can continue doing their job. So, there is latitude in areas such as that.

MR. CLARKE: This population that you're dealing with, though, is for the most part young and very physically robust, though, are they not?

CAPTAIN FULTON: That's correct.

MR. CLARKE: Thank you.

DR. GALSON: Okay. I think what we'll do is move to the Public Questions now. If we have a little bit of time, we'll circle back to the Technical Panel.

DR. ELLINGSTAD: These will probably be brief because I believe that they've been answered, but we have two questions, a statement and a comment, and the questions first.

Besides prescription and over-the-counter drugs, what is the view of the Air Force and the Navy concerning herbal use, and how is it being evaluated? I believe you spoke to that.

Is there anything you'd like to add?

(No response)

DR. ELLINGSTAD: Okay. The other question, specifically to Colonel Saenger, was, what sedative drugs are allowed for aviators for operational use, and how is their use governed?

I think you also indicated, and my understanding is, that by operational use, this would not be in the performance of the air crew duties.

COLONEL SAENGER: It's on the ground, yes.

DR. ELLINGSTAD: Okay. The statement is that the Air Force Research Lab at Brooks Air Force Base is beginning to field a drug assessment protocol using the F-PASS Performance Assessment Tool.

Would you like to comment on that?

COLONEL SAENGER: I'm not familiar with that one. I can't comment.

DR. ELLINGSTAD: Okay. Well, we can arrange a get-together afterwards, and the other comment is that a Joint Working Group, Army, Navy and Air Force, investigated terfenadine, the first non-sedating antihistamine. The process involved self-report, mood symptoms testing, physiological testing and performance testing.

Is there any comment that you would wish to make about that?

COLONEL SAENGER: I'm not familiar with that report either.

DR. ELLINGSTAD: Okay. What we will ask is, with respect to both of these things, if the submitters of these questions can provide that information for us, we'd appreciate it.

DR. GALSON: And we'll put it in the docket, and it'll be available for anybody else who wants it.

We have a few more minutes to circle back to the Technical Panel to see whether there are any remaining questions for these two witnesses.

(No response)

DR. GALSON: Okay.

DR. ANDREASON: I just had one.

DR. GALSON: Okay.

DR. ANDREASON: I just wanted to confirm that you said that SSRIs were on the not-approved list, is that correct?

COLONEL SAENGER: That's correct.

DR. ANDREASON: Or not on the approved list?

COLONEL SAENGER: They're not on the approved list.

DR. ANDREASON: Correct. Okay.

DR. GARBER: And just one follow-up question. I heard from at least one of you that medication, other kinds of prescription medications have not been found causal in military -- I think it was Air Force major mishaps.

I'm assuming that does not mean they were not found in any mishaps; they were just not identified as being causal to the mishap, is that correct?

COLONEL SAENGER: That's correct, and the data I asked for was causal.

DR. GARBER: Okay. And having been an Air Force flight surgeon myself and having investigated a number of accidents, my experience was that in many cases, the condition of the aircraft and its occupant did not permit an appropriate specimen to be evaluated to determine perhaps time of use of a medication, and therefore such a determination could not in fact be made.

Is that your experience, and is that the case with many of the aviation accidents in the military?

COLONEL SAENGER: I can't address what percent of aircraft mishaps involved such total destruction that we can't even collect the sample, but that does happen, especially --

DR. GARBER: Not just collecting a sample but collecting a sample which would give you information as to determine cause; that is to say, it may not be all that useful to have a liver sample to show us whether an individual may have been impaired by a medication.

COLONEL SAENGER: Yes, that does happen, but I don't know the rate.

DR. GALSON: Okay. We're very appreciative of how busy you are at the Defense Department, and we're very thankful that you could come by today and help us out.

With that, we'll close a few minutes early. I want to just -- just a reminder. We're going to start bright and early tomorrow, 8:00, same place, and we look forward to your continued participation.

Thanks.

(Whereupon, the meeting was adjourned, to reconvene tomorrow morning, Thursday, November 15th, 2001, at 8:00 a.m.)